Steroid compounds with a c17-alkyl side chain and an aromatic a-ring for use in therapy

ABSTRACT

Compounds of Formula (I) in which: R 1  and R 2 , which may be the same or different, each represents a lower alkyl, alkenyl or alkynyl group; R 3  represents a methyl group having α- or β-configuration; R 4  represents a hydrogen atom or an etherifying or esterifying group; R 5  represents a hydrogen atom, a hydroxyl group or a lower alkoxy group; X represents a group OR 4 , wherein R 4  is as defined above, or a group NR 6 R 7  wherein R 6  represents a hydrogen atom, an aliphatic or araliphatic organic group, or an acyl group comprising an aliphatic, araliphatic or aryl organic group linked to the nitrogen atom by way of a carbonyl group; and R 7  is a hydrogen atom or a lower alkyl group; Y represents a lower alkylene, alkenylene or alkynylene group optionally substituted by a hydroxyl, etherified hydroxyl or esterified hydroxyl group; and the dotted lines signify that double bonds may be present at the 16(17)-position and/or either at the 6(7)- and 8(9)-positions or at the 7(8)-position exhibit potent effects on modulation of cell growth and differentiation, while having low calcaemic activity.

This invention relates to novel sterol derivatives, more particularly toring A aromatic sterol derivatives in which the 17-position side chainterminates in an amino, amido or hydroxyl group and which exhibit cellmodulating activity.

It is well known that 9,10-seco sterol derivatives such as vitamin D₃play a vital role in the metabolism of calcium by promoting intestinalabsorption of calcium and phosphorus, maintaining adequate serum levelsof calcium and phosphorus, and stimulating mobilisation of calcium fromthe bone fluid compartment in the presence of parathyroid hormone.Following the discovery that D vitamins are hydroxylated in vivo, at the25-position in the liver and at the 1α-position in the kidneys, and thatthe resulting 1α,25-dihydroxy metabolite is the biologically activematerial, extensive studies have been carried out on vitamin D analogueshydroxylated at, for example, the 1α- and 24R- or 25-positions.

The natural metabolite 1α,25-dihydroxy vitamin D₃ has additionally beenfound to have effects on cellular metabolism, these cell modulatingeffects including stimulation of cell maturation and differentiation,immunosuppressive effects and immunopotentiating effects (e.g. bystimulating the production of bactericidal oxygen metabolites and thechemotactic response of leukocytes). However, the potent effects ofcompounds such as 1α,25-dihydroxy vitamin D₃ on calcium metabolism willnormally preclude their use in this area, since doses sufficient toelicit a desired cell modulating effect will tend to lead tounacceptable hypercalcaemia.

This has led to attempts to synthesize new vitamin D analogues whichhave reduced effects on calcium metabolism but which still exhibit thedesired effects on cellular metabolism. Representative examples of suchanalogues, together with summaries of earlier attempts to solve thisproblem, are given in WO-A-9309093, WO-A-9426707, WO-A-9525718 andWO-A-9516672, the contents of which are incorporated herein byreference.

It is currently believed that such vitamin D analogues act as generalregulators of cell growth and differentiation through receptor-mediated(especially nuclear receptor-mediated) processes involving modulation ofvitamin D responsive genes (M. R. Waters, Endoc. Rev. 13, pp. 719-764[1992]). It has also hitherto been assumed that the seco steroid5,7,10(19)-triene system or a similar 19-nor seco steroid 5,7-dienesystem is a prerequisite for any form of cell modulating activity. Thus,whilst workers investigating vitamin D analogues have modified theA-ring and 17-position side chain and in certain cases have made moredrastic modifications to the overall molecular skeleton such asmodification or even elimination of the C- and/or D-rings, they haveattempted to retain the triene or conjugated diene system (Gui-Dong Zhuet al., Bioorganic & Med. Chem. Lett. 6, pp. 1703-1708 [1996]; K. Sabbeet al., Bioorganic & Med. Chem. Lett. 6, pp. 1697-1702 [1996]).

Workers have recently reported the observation of non-genomic rapidresponses to vitamin D analogues which they attribute to interactionwith a putative cell membrane-located vitamin D receptor (A. W. Normanet al., J. Steroid Biochem. and Mol. Biol. 56, pp. 13-22 [1996]). It hasalso been reported that such non-genomic rapid effects may be elicitedby 1α,3β,25-trihydroxycholesta-5,7-diene, i.e. the pro-vitamin form of1α,25-dihydroxy vitamin D₃, which is not a seco steroid; this has beenattributed to the ability of the pro-vitamin to mimic the 6,7-s-cisconformation of the normal vitamin D triene (Norman, op. cit.). However,the pro-vitamin has been reported to have little ability to elicit thegenomic effect believed to underlie modulation of cell growth anddifferentiation (Norman, op. cit.) and has also been reported not toexhibit the typical effects of vitamin D on skin (R. Gniadecki et al.,British J. Dermatol. 132, pp. 841-852 [1995]).

The present invention is based on the surprising finding that a range ofsimple sterol derivatives which have an intact tetracyclic nucleus andlack both the seco steroid triene system of vitamin D analogues and theability to mimic a conjugated conformational isomer thereof, exhibitpotent effects on the modulation of cell growth and differentiation, forexample as demonstrated by their ability to inhibit growth of cancercells in vitro and in vivo, and their ability to promote the healing ofear punches in vivo. The compounds possess an advantageous therapeuticratio by virtue of their low levels of calcaemic activity, for exampleas determined by their effects on serum calcium and phosphorus levels inrats.

The compounds of the invention comprise 3-sterols (and O-protectedderivatives thereof) having an aromatic A ring and an amine-, amide- orhydroxyl-terminated 17-position side chain. The compounds may alsocontain an aromatic B-ring or a double bond at the 7(8)-position and/ora double bond at the 16(17)-position.

Thus according to one embodiment of the invention there are providedcompounds of formula (I)

in which:

-   -   R¹ and R², which may be the same or different, each represents a        lower alkyl, alkenyl or alkynyl group;    -   R³ represents a methyl group having α- or β-configuration;    -   R⁴ represents a hydrogen atom or an etherifying or esterifying        group;    -   R⁵ represents a hydrogen atom, a hydroxyl group or a lower        alkoxy group;    -   X represents a group OR⁴, wherein R⁴ is as defined above, or a        group NR⁶R⁷ wherein R⁶ represents a hydrogen atom, an aliphatic        or araliphatic organic group, or an acyl group comprising an        aliphatic, araliphatic or aryl organic group linked to the        nitrogen atom by way of a carbonyl group; and R⁷ is a hydrogen        atom or a lower alkyl group;    -   Y represents a lower alkylene, alkenylene or alkynylene group        optionally substituted by a hydroxyl, etherified hydroxyl or        esterified hydroxyl group; and    -   the dotted lines signify that double bonds may be present at the        16(17)-position and/or either at the 6(7)- and 8(9)-positions or        at the 7(8)-position.

R¹ and R² may, for example, be selected from lower (e.g. C₁₋₆) alkylgroups such as methyl, ethyl, propyl and butyl groups, lower (e.g. C₂₋₇)alkenyl groups such as allyl, and lower (e.g. C₂₋₇) alkynyl groups suchas propargyl. Where appropriate the groups may be straight chain orbranched; straight chain groups may be preferred.

Where R³ in formula (I) is a methyl group in the α-configuration, thecompounds have the 20R configuration characteristic of natural sterolssuch as cholesterol; where R³ is in the β-configuration the compoundshave the 20S configuration of the corresponding epi-derivatives. It willbe appreciated that the invention also embraces mixtures of the twoisomers.

Where R⁴ represents an etherifying or an esterifying group this may, forexample, comprise any suitable cleavable O-protecting group such as iscommonly known in the art. Such O-protected derivatives of compounds offormula (I) are useful in the preparation of active compounds (I) inwhich R⁴ represents a hydroxy group and may also, where the O-protectinggroup is either metabolically labile in vivo or is a lower alkyletherifying group such as methyl, ethyl or isobutyl, be useful directlyin therapy. Representative O-protecting groups include (i) etherifyinggroups such as silyl groups (e.g. tri(lower alkyl)silyl groups such astrimethylsilyl, triethylsilyl, triisopropylsilyl ort-butyldimethylsilyl; tri(aryl)silyl groups such as triphenylsilyl; andmixed alkyl-arylsilyl groups), lower (e.g. C₁₋₆) alkyl groups optionallyinterrupted by one or more oxygen atoms (e.g. such as methyl, ethylmethoxymethyl or methoxyethoxymethyl) or substituted by a lower (e.g.C₂₋₈) cycloalkyl group (e.g. as in cyclopentylmethyl), and cyclic ethergroups (e.g. such as tetrahydropyranyl), and (ii) esterifying groupssuch as lower (e.g. C₁₋₆) alkanoyl (e.g. such as acetyl, propionyl,isobutyryl or pivaloyl), aroyl (e.g. containing 7-15 carbon atoms, suchas benzoyl or 4-phenylazobenzoyl), lower (e.g. C₁₋₆) alkane sulphonyl(e.g. such as methane sulphonyl or halogenated methane sulphonyl) andarene sulphonyl (e.g. such as p-toluene sulphonyl). Where appropriatethe groups may be straight chain or branched.

Where R⁵ represents a lower alkoxy group, this may for example be astraight chain or branched C₁₋₆ alkoxy group such as a methoxy, ethoxyor propoxy group.

Where R⁶ represents an aliphatic group this may, for example, be a loweralkyl group, for example a straight chain C₁₋₆ alkyl group such as amethyl, ethyl, propyl or butyl group. Araliphatic groups R⁶ may, forexample, include C₆₋₁₂ carbocyclic aryl C₁₋₄ alkyl groups such as benzylor phenethyl. Where R⁶ represents an acyl group this may, for example,be a lower (e.g. C₁₋₆) alkanoyl group such as formyl, acetyl orpropionyl; a C₆₋₁₂ carbocyclic aryl C₂₋₅ alkanoyl group such asphenylacetyl; or a C₇₋₁₃ carbocyclic aroyl group such as benzoyl. Thegroup R⁶ may optionally carry one or more substituents, for exampleselected from halo (e.g. chloro or bromo), lower (e.g. C₁₋₄) alkyl suchas methyl, lower alkoxy (e.g. methoxy), lower alkanoyl (e.g. acetyl),lower alkylamino (e.g. methylamino), di(lower alkyl)amino (e.g.dimethylamino), nitro, carbamoyl and lower alkanoylamino (e.g.acetamido).

When R⁷ represents a lower alkyl group, this may, for example, be astraight chain or branched C₁₋₆ alkyl group such as a methyl, ethyl,propyl or butyl group.

Lower alkylene, alkenylene or alkynylene groups represented by Y may,for example, contain up to 7 carbon atoms and up to 3 multiple bonds. Ymay advantageously be a straight chain group, e.g. containing 2-6 carbonatoms, for example as in ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, vinylene, buta-1,3-dienylene, propynylene(e.g. prop-2-ynylene), but-1-ynylene or but-2-ynylene.

Where Y is substituted by a hydroxyl, etherified hydroxyl or esterifiedhydroxyl group, this substituent may advantageously be positioned α-, β-or γ- to the group —C(R¹)(R²).X or α- to any triple bond present in thegroup Y, e.g. as in 1-hydroxyprop-2-ynylene. Etherifying groups whichmay be present include lower (e.g. C₁₋₆) alkyl groups optionallyinterrupted by one or more oxygen atoms (e.g. methyl, methoxymethyl ormethoxyethoxymethyl), and cyclic groups such as tetrahydropyranyl.Esterifying groups which may be present include lower (e.g. C₁₋₆)alkanoyl such as acetyl, propionyl, isobutyryl or pivaloyl; loweralkenoyl (e.g. allylcarbonyl); aroyl (e.g. p-nitrobenzoyl); loweralkoxycarbonyl (e.g. t-butoxycarbonyl); lower haloalkoxycarbonyl (e.g.2,2,2-trichloroethoxycarbonyl or1,1,1-trichloro-2-methyl-2-propoxycarbonyl); aralkyloxycarbonyl (e.g.benzyloxycarbonyl or p-nitrobenzyloxycarbonyl); and loweralkenyloxycarbonyl (e.g. allyloxycarbonyl). It will be appreciated thatit may be advantageous to select etherifying or esterifying groups whichare metabolically labile in vivo.

The cell modulating activity of compounds according to the invention,including O-protected derivatives in which the O-protecting group ismetabolically labile, combined with their substantial lack of calcaemiceffect, render them of interest both alone and as adjuncts in themanagement of diseases associated with abnormal cell proliferation, suchas neoplastic disease, particularly myelogenous leukemias as well asneoplastic disease of the brain, breast, stomach, gastrointestinaltract, prostate, pancreas, uro-genital tract (male and female) andpulmonary neoplasia. Their ability to promote closure of mouse earpunches suggests their use, either alone or as adjuncts, as agents topromote wound healing. Compounds of the invention also appear to promotehealing of experimental burns, suggesting a utility in burn management.The cell modulating activity of compounds of the invention suggests thatthey may, like vitamin D analogues, have additional utilities eitheralone or as adjuncts in the chemotherapy of infection and in othertherapeutic modalities in which mononuclear phagocytes are involved, forexample in treatment of bone disease (e.g. osteoporosis, osteopenia andosteodystrophy as in rickets or renal osteodystrophy), autoimmunedisease, host-graft reaction, transplant rejection, inflammatorydiseases (including modulation of immunoinflammatory reactions),neoplasias and hyperplasias, myopathy, enteropathy and spondylitic heartdisease, their potential utility in treatment of neoplasias andhyperplasias being evidenced by their ability to inhibit human cancerxenografts in severe combined immunodeficiency mice. Additionally, theymay be useful in suppression of parathyroid hormone (e.g. as in serumcalcium homeostasis), in treatment of dermatological diseases (forexample including acne, alopecia, eczema, pruritus, psoriasis and skinaging, including photoaging), hypertension, rheumatoid arthritis,psoriatic arthritis, secondary hyperparathyroidism, asthma, cognitiveimpairment and senile dementia (including Alzheimer's disease), infertility control in both human and animal subjects, and in managementof disorders involving blood clotting (e.g. by dissolution of existingclots and/or by prevention of clotting). The invention embraces use ofthese compounds in the therapy or prophylaxis of such conditions and inthe manufacture of medicaments for use in such treatment or prophylaxis.

Compounds of the invention have also been found to bind to oestrogenreceptors, whilst being free from and even inhibiting uterotrophiceffects such as are associated with conventional oestrogens. Thisbinding effect, in combination with their anabolic wound healingeffects, suggests that such compounds may additionally be useful inprevention or treatment of osteoporosis and in reduction of serumcholesterol.

Active compounds according to the invention may be formulated foradministration by any convenient route, e.g. orally (includingsublingually), parenterally, rectally or by inhalation; pharmaceuticalcompositions so formulated comprise a feature of the invention.

Orally administrable compositions may, if desired, contain one or morephysiologically compatible carriers and/or excipients and may be solidor liquid. The compositions may take any convenient form including, forexample, tablets, coated tablets, capsules, lozenges, aqueous or oilysuspensions, solutions, emulsions, syrups, elixirs and dry productssuitable for reconstitution with water or another suitable liquidvehicle before use. The compositions may advantageously be prepared indosage unit form. Tablets and capsules according to the invention may,if desired, contain conventional ingredients such as binding agents, forexample syrup, acacia, gelatin, sorbitol, tragacanth orpolyvinyl-pyrollidone; fillers, for example lactose, sugar,maize-starch, calcium phosphate, sorbitol or glycine; lubricants, forexample magnesium stearate, talc, polyethylene glycol or silica;disintegrants, for example potato starch; or acceptable wetting agentssuch as sodium lauryl sulphate. Tablets may be coated according tomethods well known in the art.

Liquid compositions may contain conventional additives such assuspending agents, for example sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxymethylcellulose,carboxymethylcellulose, aluminium stearate gel or hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate oracacia; non-aqueous vehicles, which may include edible oils, for examplevegetable oils such as arachis oil, almond oil, fractionated coconutoil, fish-liver oils, oily esters such as polysorbate 80, propyleneglycol, or ethyl alcohol; and preservatives, for example methyl orpropyl p-hydroxybenzoates or sorbic acid. Liquid compositions mayconveniently be encapsulated in, for example, gelatin to give a productin dosage unit form.

Compositions for parenteral administration may be formulated using aninjectable liquid carrier such as sterile pyrogen-free water, sterileperoxide-free ethyl oleate, dehydrated alcohol or propylene glycol or adehydrated alcohol/propylene glycol mixture, and may be injectedintravenously, intraperitoneally or intramuscularly.

Compositions for rectal administration may be formulated using aconventional suppository base such as cocoa butter or another glyceride.

Compositions for administration by inhalation are convenientlyformulated for self-propelled delivery, e.g. in metered dose form, forexample as a suspension in a propellant such as a halogenatedhydrocarbon filled into an aerosol container provided with a meteringdispense valve.

It may be advantageous to incorporate an antioxidant, for exampleascorbic acid, butylated hydroxyanisole or hydroquinone in thecompositions of the invention to enhance their storage life.

Where any of the above compositions are prepared in dosage unit formthese may for example contain 10 μg -100 mg, preferably 100 μg -100 mgof active compound according to the invention per unit dosage form; suchdosage units may for example be administered 1-4 times per day. Thecompositions may if desired incorporate one or more further activeingredients.

A suitable daily dose of an active compound according to the inventionmay for example be in the range 100 μg -400 mg, per day, depending onfactors such as the severity of the condition being treated and the age,weight and condition of the subject.

Compounds according to the invention may be prepared by any convenientmethod, for example by reaction of a compound containing a precursor forthe desired 17-position side chain in one or more stages and with one ormore reactants serving to form the said desired 17-position side chain,followed if necessary and/or desired by removal of any O-protectinggroup.

Appropriate techniques for formation of a desired side chain includethose described in the aforementioned WO-A-9516672.

Thus, for example, in order to prepare a compound (I) in which R¹ and R²are identical and X is the group NR⁶R⁷ in which R⁶ and R⁷ are hydrogenatoms, a compound of general formula (II)

(where R³, R⁴, R⁵ and Y are as hereinbefore defined) may be reacted withan organo-cerium reagent, e.g. prepared in situ from cerous chloride andan appropriate organometallic compound, e.g. an alkyl/cycloalkyl lithiumcompound of formula R¹Li (where R¹ is as hereinbefore defined), forexample as described by Ciganek (J. Org. Chem. 57, pp. 4521-4527[1992]).

Compounds of formula (I) in which R¹ and R² are different and X is thegroup NR⁶R⁷ in which R⁶ and R⁷ are hydrogen atoms may, for example, beprepared by reacting a thio-oxime of formula (III)

(where R¹, R³, R⁴, R⁵ and Y are as hereinbefore defined and R⁸ is anaromatic group, e.g. a carbocyclic aryl group such as phenyl) with anappropriate organometallic compound, for example an alkyl/cycloalkyllithium compound of formula R²Li (where R² is as hereinbefore defined),and reducing the thus-obtained compound of formula (IV)

(where R¹, R², R³, R⁴, R⁵, R⁸ and Y are as hereinbefore defined), e.g.using a metal hydride reducing agent such as sodium borohyride or aninorganic or organic sulphur compound such as hydrogen sulphide, sodiumsulphide or a thiol (e.g. a lower alkyl mercaptan such as methanethiol)to remove the R⁸.S group and yield a corresponding compound of formula(I) in which X is the group NR⁶R⁷ in which R⁶ and R⁷ represent hydrogenatoms (see J. Org. Chem. 42, pp. 398-399 [1977]).

Compounds of formula (I) where X is a group NR⁶R⁷ in which R⁶ representsa lower alkanoyl, aralkanoyl or aroyl group and R⁷ represents a hydrogenatom may be prepared by acylation of a corresponding compound (I) inwhich R⁶ is hydrogen, for example by reaction with an appropriate acylhalide or acid anhydride, preferably in the presence of water or a loweralcohol, as may typically be incorporated to suppress acylation ofgroups other than the amino group, or with an appropriate acid in thepresence of a coupling agent such as N,N′-carbonyl-diimidazole ordicyclohexylcarbodiimide. It will be appreciated that if the acylationis carried out in the absence of components such as water or loweralcohols which suppress the acylation of hydroxyl groups, then anyhydroxyl groups present in the molecule, e.g. at the 2- or 3-position oras a substituent of the Y group, should desirably be in O-protected formduring such an acylation reaction.

Compounds of formula (I) where X is a group NR⁶R⁷ in which R⁶ representsan aliphatic or araliphatic group and R⁷ represents a hydrogen atom may,for example, be prepared by reducing a corresponding compound (I) inwhich R⁶ is an aliphatic or araliphatic acyl group, e.g. using a metalhydride reducing agent such as lithium aluminium hydride.

Compounds of formula (I) where X is a group NR⁶R⁷ in which at least oneof R⁶ and R⁷ represents a hydrogen atom may be subjected to appropriatesubstitution reactions to introduce desired R⁶ and/or R⁷ groups, forexample to direct alkylation, e.g. by reaction with an alkyl halide, orto reductive amination, e.g. by reaction with an appropriate aldehydeand a reducing agent such as sodium cyanoborohydride.

Compounds of formula (I) in which X is a hydroxyl group may, forexample, be prepared by reaction of a compound of formula (V)

(where R¹, R³, R⁴, R⁵ and Y are as hereinbefore defined) with anappropriate organometallic compound, for example a compound of formulaR²Li (where R² is as hereinbefore defined).

Compounds of formula (I) in which X is a hydroxyl group and R¹ and R²are identical may similarly be prepared by reaction of a compound offormula (VI)

(where R³, R⁴, R⁵ and Y are as hereinbefore defined and R⁹ is a lower[e.g. C₁₋₆] alkyl group such as methyl, ethyl, isopropyl or isoamyl)with an excess of an appropriate organometallic compound, for example acompound of formula R¹Li (where R¹ is as hereinbefore defined and isidentical to R²).

Compounds of formula (I) in which Y is an alkynylene group may, forexample, be prepared by reaction of a compound of formula (VII)

(where R³, R⁴ and R⁵ are as hereinbefore defined; Y^(a) is an alkylenegroup, e.g. containing 1-4 carbon atoms; and L represents a leavinggroup, for example a sulphonate ester group, e.g. lower alkylsulphonyloxy such as mesyloxy, lower fluoroalkyl sulphonyloxy such astrifluoromethanesulphonyloxy or aryl sulphonyloxy such as tosyloxy, or ahalogen atom such as chlorine, bromine or iodine), with a metallatedderivative (e.g. the lithio derivative) of an alkyne of formula (VIII)

(where R¹, R² and X are as hereinbefore defined and n is 0 or aninteger, e.g. in the range 1-3).

The thus obtained compound (I) in which Y is the group—Y^(a)—C≡C—(CH₂)_(n)—(wherein Y^(a) and n are as hereinbefore defined) may if desired behydrogenated to convert the triple bond either to a double bond (e.g.using Lindlar catalyst) or to a single bond (e.g. using a noble metalcatalyst such as platinum, palladium or homogeneous rhodium orruthenium).

Compounds of formula (I) in which Y is an alkynylene group carrying ahydroxyl group a to the triple bond may, for example, be prepared byreaction of a compound of formula (IX)

(where R³, R⁴ and R⁵ are as hereinbefore defined and Y^(b) is a valencebond or an alkylene group, e.g. containing 1-4 carbon atoms) with ametallated derivative of an alkyne of formula (VIII), so as to form acompound (I) in which Y is a group—Y^(b)—CH(OH)—C≡C—(CH₂)_(n)—(wherein Y^(b) and n are as hereinbefore defined).

Compounds of formula (VIII) may be prepared by subjecting a compound offormula (X)CH₃(CH₂)_(n)C≡C—C(R¹)(R²)OH  (X)(where n, R¹ and R² are as hereinbefore defined) to a Ritter reactionwith a compound of formula R^(a)CN (where R^(a) represents a hydrogenatom or an appropriate organic group) in the presence of a strong acid,e.g. a mineral acid such as sulphuric acid, thereby leading to formationof a compound (I) where X is the group NR⁶R⁷ in which R⁶ represents agroup R^(a).CO— and R⁷ is a hydrogen atom. The R⁶ group may be removedby hydrolysis to yield a compound (I) in which R⁶ represents a hydrogenatom or may be reduced, e.g. as hereinbefore described, to yield acompound (I) in which R⁶ represents a group R^(a).CH₂—. Alternativelythe hydroxyl group of the tertiary carbinol may be displaced by an azidogroup, e.g. by reaction with hydrazoic acid in the presence of a strongacid, and the azido group reduced to yield a compound (I) where X is thegroup NR⁶R⁷ in which R⁶ and R⁷ represent hydrogen atoms. The internalalkyne group may then be isomerized to the terminal position bytreatment with the potassium salt of 1,3-propanediamine in1,3-propanediamine as solvent (“acetylene zipper”).

Compounds of formula (II) may, for example, themselves be prepared byreaction of a compound of formula (VII) as defined above with, asappropriate, (i) a source of cyanide ion (e.g. an alkali metal cyanidesuch as sodium or potassium cyanide), (ii) a metallated acetonitrilederivative (e.g. the lithio derivative), or (iii) acrylonitrile,preferably where L is an iodine atom (e.g. by ultrasound-inducedchromium-mediated conjugate addition as described by Mourino et al. inJ. Org. Chem. 58, pp. 118-123 [1993]).

Compounds (II) in which the 17-position side chain terminates in thegroup —CH:CH.CN may, for example, be prepared from an aldehyde offormula (IX) as defined above by means of a Wittig reaction with an ylidof formula (R¹⁰)₃P:CH.CN (where each R¹⁰ represents an organic group,e.g. a carbocyclic aryl group such as phenyl) or with a correspondingphosphonate or silyl equivalent.

Compounds of formula (III) may, for example, themselves be prepared byreacting a ketone of formula (V) with an S-substituted thiolamine offormula R⁸.S.NH (where R⁸ is as hereinbefore defined). Such compounds offormula (V) may, for example, be prepared from an acid of formula (XI)

(where R³, R⁴, R⁵ and Y are as hereinbefore defined), e.g. by formationof a corresponding acid halide such as the chloride and reaction with anorganometallic compound R¹MX (where R¹ is as hereinbefore defined; Mrepresents a divalent metal such as copper, zinc or cadmium; and Xrepresents e.g. a halogen atom). Alternatively one may prepare compounds(V) by reacting a compound of formula (VII) above with e.g. (i) anα-metallated derivative such as a lithio derivative of a ketone offormula CH₃.CO.R¹ (where R¹ is as hereinbefore defined) or with acorresponding enol, or (ii), preferably where L is an iodine atom, avinyl ketone of formula CH₂:CH.CO.R¹ (where R¹ is as hereinbeforedefined), e.g. by ultrasound-induced chromium-mediated conjugateaddition as described by Mourino et al. (op. cit.).

Compounds (XI) and esters thereof, e.g. compounds of formula (VI), mayalso be used to prepare compounds of formula (II) by reaction withammonia or a metallated derivative thereof, e.g. an alkali metal amidesuch as lithium amide, to form a corresponding carboxamide which may beconverted to a nitrile (II) by mild dehydration, e.g. using tosylchloride, phosphorus oxychloride in the presence of a base such aspyridine, or trifluoracetic anhydride in the presence of an excess of abase such as pyridine.

Compounds (II) in which Y is α-substituted by a hydroxyl group areconveniently obtained by cyanohydrin formation, for example by reactionof a compound (IX) with hydrogen cyanide. Compounds (II) in which Y isβ-substituted by a hydroxyl group may be prepared directly by reactionof a compound (IX) with a metallated (e.g. lithiated) derivative ofacetonitrile; they may also be prepared indirectly by reaction with ametallated derivative of an ester of acetic acid, followed by conversionof the ester group to a carboxamide group and then to a nitrile group,e.g. as described above.

In general compounds (I) and starting materials therefor in which Y issubstituted by a hydroxyl group may be converted to corresponding etherand ester derivatives by standard methods such as are well known in theart. Thus, for example, etherification may be effected by reaction withan appropriate organic halide (e.g. an alkyl iodide) in the presence ofan appropriate base (e.g. an alkali metal alkoxide such as potassiumt-butoxide), advantageously in the presence of a crown ether such as18-crown-6. Esterification may be effected by reaction with appropriateacylating agents, such as acyl halides, acid anhydrides and the like.

Compounds of formula (VII) may be prepared from estrone, equilenin orequilin as appropriate by, for example, Wittig reaction with anethylidene phosphorane to convert the 17-one to the correspondingZ-17(20) ethylidene compound, following the procedure described byKrubiner and Oliveto, J. Org. Chem. 31, pp. 24-26 [1965]. Alternatively,the corresponding E-isomer may be obtained following the procedure ofMidland and Kwon, Tetrahedron Lett. 23(20), pp. 2077-2080 [1982]. Thethus-obtained alkenes may be subjected to conventional stereospecifichydroboration reactions followed by oxidative work-up with alkalinehydrogen peroxide solution (Krubiner, op. cit.) to afford thecorresponding 20-ols, which may be oxidised to 20-ones with chromiumtrioxide (Krubiner, op. cit.). Wittig reaction withmethoxymethylenetriphenylphosphorane, hydrolysis of the enol ether withaqueous acid (to give a non-stereospecific aldehyde of formula (IX) inwhich Y^(b) represents a valence bond), reduction with sodiumborohydride and reaction of the resulting alcohol with tosyl chlorideaffords compounds of formula (VII) wherein R³ is methyl, Y^(a) ismethylene and L is tosyloxy.

Compounds of formula (VII) having a double bond at the 16(17)-positionmay, for example, be prepared stereospecifically by subjecting theappropriate E- or Z-17(20) ethylidene compound prepared as describedabove to a stereospecific ene reaction. For example, such ene reactionsinclude treatment with formaldehyde, boron trifluoride and optionallyacetic anhydride (Batcho et al., Helv. Chim. Acta 64, pp. 1682-1687[1981]) to form compounds of formula (VII) in which R³ is methyl, Y^(a)is methylene and L is hydroxy or acetoxy. The acetyl group may beremoved by hydrolysis and the hydroxyl group may be tosylated togenerate a compound (VII) in which L is a suitable leaving group. In analternative ene reaction, treatment with ethyl propiolate/diethylaluminium chloride (Dauben and Brookhart, J. Am. Chem. Soc. 103, pp.237-238 [1980]) affords ethyl esters of Δ16,17 acids of general formula(XI) in which R³ is methyl and Y is ethylene, from which thecorresponding free acid may be obtained by hydrolysis. The Δ16,17compounds described above may be stereospecifically hydrogenated.

Compounds of formula (VII) in which Y^(a) is e.g. ethylene ortrimethylene may, for example, be obtained by reaction of a compound(VII) in which Y^(a) is methylene either (i) with a reagent serving tointroduce a one-carbon fragment (e.g. a metal cyanide) and conversion ofthe group so introduced to a group —CH₂L, e.g. by hydrolysing a cyanogroup to yield a carboxy group or by reducing such a cyano group (e.g.with a metal hydride reducing agent such as diisobutyl aluminiumhydride) to yield a carboxaldehyde group, and reducing the carboxy orcarboxaldehyde group (e.g. using sodium borohydride or lithium aluminiumhydride) to yield a hydroxymethyl group which may in turn be subjectedto tosylation and, if desired, nucleophilic displacement as hereinbeforedescribed to effect conversion to a halomethyl group; or (ii) with ametallated derivative of an ester or thioester of acetic acid, with aderivative containing another carbanionic equivalent of acetic acid(e.g. a metallated derivative of acetonitrile), or with a metallatedmalonate ester (in which last instance the reaction product is partiallyhydrolysed to yield a monoester which may be decarboxylated by heatingto yield a carboxylate ester), reducing the resulting ester or thioesterproduct to an alcohol (e.g. using lithium aluminium hydride), andconverting the resulting hydroxyl group to a leaving group, such as atosylate group or a halogen atom, e.g. as hereinbefore described.

It will be appreciated that the above procedures (i) and/or (ii) may berepeated as needed to yield compounds (VII) in which Y^(a) is a C₃₋₇alkylene group.

In general, O-protecting groups may, for example, be removed byconventional methods such as are well documented in the literature. Thusesterifying acyl groups may be removed by basic hydrolysis, e.g. usingan alkali metal alkoxide in an alkanol. Etherifying groups such as silylgroups may be removed by acid hydrolysis or treatment with a fluoridesalt, e.g. a tetraalkyl ammonium fluoride. The use of such acid-labilebut base-stable protecting groups may be of particular advantage duringhomologation steps to build up a desired side chain, in view of thestrongly basic conditions normally employed for such reactions.

The following non-limitative examples serve to illustrate the invention.All temperatures are in °C.

Preparation 1

a) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10),16-tetraen-24-ol[Formula (VII): R³=α-CH₃, R⁴=(i—Pr)₃Si, R⁵=H, Y^(a)=(CH₂)₃, L=OH, Δ16double bond]

A solution of3-triisopropylsilyloxy-19-nor-chol-1,3,5(10),16,22-pentaene-24-carboxylicacid methyl ester [Formula (VII)—R³=α-CH₃, R⁴=(i-Pr)₃Si, Y^(a)=—CH═CH—,L=CO.OCH₃, Δ16 double bond] (177 mg—prepared by silylation of thecorresponding 3-hydroxy compound) in ether (6.5 ml) was added dropwiseto a solution of lithium aluminium hydride in ether (3 ml of a 1Msolution). The mixture was stirred for 3 hours and worked up to affordthe title compound as an approximately 85/15 mixture with thecorresponding Δ22 compound.

b) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10),16-tetraen-24-ol,24-tosylate [Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y^(a)=(CH₂)₃,L=O,SO₂,C₆H₄,CH₃, Δ16 double bond]

A solution containing the mixture of alcohols from (a) above (223 mg),tosyl chloride (216 mg) and pyridine (476 μl) in methylene chloride (4ml) was stirred at room temperature for 4 hours, treated with aqueoussodium bicarbonate solution, stirred overnight, and worked up to afforda mixture of the Δ22 alcohol and the title compound (190 mg): NMR(CDCl₃) δ 0.85 (s, 18-H's), 2.65 (s, tosyl-Me), 3.9 (t, 24-H's), 5.1(bs, 16-H), 6.5 and 6.95 (m, 1-, 2- and 4-H's), 7.65 and 7.62 (ABq,tosyl-H's).)

c) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10),16-tetraene-24-bromide[Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y^(a)=(CH₂)₃, L=Br, Δ16double bond]

The 24-tosylate from (b) above (190 mg) in 1,2-dichloroethane (5 ml) andacetonitrile (5 ml) containing lithium bromide (300 mg) was heated underreflux for 3 hours. The reaction mixture was then cooled, diluted withethyl acetate, washed with water then brine, and dried over sodiumsulphate. Evaporation of the solvent gave the title compound (156 mg):NMR (CDCl₃) δ 0.9 (s, 18-H's), 3.5 (t, 24-H's), 5.2 (bs, 16-H), 6.5 and6.95 (m, 1-, 2-, and 4-H's).

Preparation 2

a) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10)-triene-24-carboxylicacid methyl ester [Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H,Y^(a)=(CH₂)₂, L=CO,OCH₃]

A solution of the Δ16, Δ22-pentaenic acid methyl ester used as startingmaterial in Preparation 1(a) (200 mg) in ethyl acetate (10 ml) wastreated with palladium/charcoal (400 mg, 10%) and stirred overnightunder an atmosphere of hydrogen. Filtration through Celite and removalof the solvent under reduced pressure afforded the title compound (177mg): NMR (CDCl₃) δ 0.96 (s, 18-H's), 3.7 (s, ester CH₃), 6.5 and 6.95(m, 1-, 2- and 4-H's) (peaks at δ 5.2 and 5.6-5.9 were absent).

b) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10)-trien-24-ol [Formula(VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y^(a)=(CH₂)₃, L=OH]

The ester from (a) above (177 mg) was treated with lithium aluminiumhydride (3 ml of a 1M solution in ether) for 3 hours at roomtemperature. The resulting product was worked up to give the titlecompound (158 mg): NMR (CDCl₃) δ 3.9 (t, 24-H's), 6.5 and 6.95 (m, 1-,2- and 4-H's) (peak at δ 3.8 was absent).

c) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10), triene-24-bromide[Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y^(a)=(CH₂)₃, L=Br]

Treatment of the alcohol from (b) above (158 mg) with tosyl chloride asin Preparation 1(b), followed by treatment of the resulting toluenesulphonate (176 mg) with lithium bromide as in Preparation 1(c) affordedthe title compound (131 mg): NMR (CDCl₃) δ 0.96 (s, 18-H's), 3.4 (t,24-H's), 6.5 and 6.95 (m, 1-, 2- and 4-H's).

Preparation 3

a)3-Triisopropylsilyloxy-20α-acetoxymethyl-19-nor-pregn-1,3,5(10),16-tetraene[Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y^(a)=CH₂, L=O,CO,CH₃, Δ16double bond]

A mixture of boron trifluoride etherate (50 μl) and acetic anhydride(0.6 ml) in dichloromethane (0.6 ml) was added dropwise to a solution of3-triisopropylsilyloxy-19-nor-pregn-1,3,5(10),17(20)Z-tetraene (1.8 g)in dichloromethane (2 ml) containing acetic anhydride (0.9 ml) andparaformaldehyde (120 mg). The mixture was stirred for 2 hours,whereafter saturated sodium hydrogen carbonate was added and stirringwas continued for 2 hours. The product was isolated by extraction intodichloromethane and purified by chromatography to give the titlecompound (1.5 g).

b)3-Triisopropylsilyloxy-20α-hydroxymethyl-19-nor-pregn-1,3,5(10)-triene[Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y^(a)=CH₂, L=OH, Δ16double bond]

A solution of the product from (a) above (1.2 g) in ethanol (20 ml)containing 5% platinum on carbon (240 mg) was stirred under hydrogen for2 days. Filtration and removal of the solvent afforded the 20-acetate ofthe title product (1.15 g), 480 mg of which was reduced with lithiumaluminium hydride (1.2 ml of 1 M solution in ether) in ether (10 ml) togive the title compound (440 mg): IR (CDCl₃) υ_(max) 1600, 3280 cm⁻¹;NMR (CDCl₃) δ 0.7 (s, 18-H's), 6.3-7.2 (m, 1-, 2- and 4-H's).

c)3-Triisopropylsilyloxy-20α-tosyloxymethyl-19-nor-pregn-1,3,5(10)-triene[Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y^(a)=CH₂,L=O,SO₂,C₆H₄,CH₃]

A solution of the alcohol from step (b) above (440 mg) indichloromethane (2 ml) containing pyridine (0.5 ml) and tosyl chloride(445 mg) was stirred at room temperature overnight. The reaction mixturewas then treated with aqueous sodium hydrogen carbonate and stirred fora further 2 hours, whereafter the product was extracted intodichloromethane and the extract was washed successively with water, 3%phosphoric acid and brine. Removal of the solvent followed bychromatography gave the title compound (485 mg): IR (CDCl₃) υ_(max) 1600cm⁻¹; NMR (CDCl₃) δ 0.66 (s, 18-H's), 2.33 (s, tosyl-Me), 3.5-4.2 (bm,22-H's), 6.3-7.0 (m, 1-, 2- and 4-H's), 7.0, 7.9 (m, tosyl aryl-H's).

d) 3-Triisopropylsilyloxy-20α-bromomethyl-19-nor-pregn-1,3,5(10)-triene[Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y^(a)=CH₂, L=Br]

The tosylate from step (c) above (485 mg) in a mixture of acetonitrile(16 ml) and dichloroethane (16 ml) containing lithium bromide (654 mg)was stirred overnight; water was then added and the product wasextracted into dichloroethane. The extract was washed and dried, and thesolvent was removed to give the title compound (360 mg). This productwas used in further steps without further purification.

Preparation 4

3-Triisopropylsilyloxy-20α-formyl-19-nor-pregn-1,3,5(10)-triene [Formula(IX): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y^(b)=valence bond]

The 20-hydroxymethyl compound from Preparation 3(b) (220 mg) was stirredwith pyridinium dichromate (1.25 mmol) in dichloromethane (3 ml) for 2hours. Residual reagent was filtered off, the solvent was removed andthe resulting material was purified by preparative thin layerchromatography (PTLC) to give the title compound (120 mg): IR (CDCl₃)υ_(max) 1600, 1710 cm⁻¹; NMR (CDCl₃) δ 0.7 (s, 18-H's), 6.3-7.2 (m, 1-,2- and 4-H's), 9.3,9.5 (d, CHO).

Preparation 5

2-Methoxy-3-triisopropylsilyloxy-19-nor-pregn-1,3,5(10),17(20)Z-tetraene

Sodium hydride (294 mg, 50%) in dimethylsulphoxide (6 ml) was stirred at70° C. for 1 hour, then cooled to room temperature.Ethyltriphenylphosphonium iodide (2.75 g) in dimethylsulphoxide (10 ml)was added dropwise and the resulting mixture was stirred for 30 minutes.A solution of 2-methoxy-estrone-3-triisopropylsilyl ether (600 mg,prepared by silylation of the 3-OH compound with triisopropylsilylchloride and imidazole in dichloromethane overnight at room temperature)in dimethylsulphoxide (10 ml) was added dropwise. The resulting solutionwas stirred for 30 minutes, whereafter the temperature was raised to 70°and stirring was continued overnight. The reaction mixture was cooledand worked up. Separation and purification of the products bychromatography gave the title compound (125 mg, see below) and the 3-OHanalogue (300 mg): IR (CDCl₃) υ_(max) 1590, 3520 cm⁻¹; NMR (CDCl₃) δ 0.9(s, 18-H's), 1.67 (d, ═CH—CH's), 3.8 (s, OCH's), 4.7-5.2 (q, ═CHMe),6.5, 6.7 (s, 1,4-H's).

Silylation of this 3-OH compound (300 mg) as above and purification ofthe product by chromatography gave the title compound (370 mg): IR(CDCl₃) υ_(max) 1600 cm⁻¹; NMR (CDCl₃) δ 0.9 (s, 18-H's), 1.68 (d,═CH—CH's), 3.7 (s, OCH's), 4.7-5.3 (q, ═CH—Me), 6.4, 6.6 (s, 1,4-H's).

Preparation 6

a)2-Methoxy-3-triisopropylsilyloxy-19-nor-chol-1,3,5(10),16-tetraene-24-carboxylicacid methyl ester [Formula (VI): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=OCH₃,R9=CH3, Y=(CH₂)₂, Δ16 double bond]

Ethyl aluminium dichloride (1.4 ml, 2.4 mmol, in toluene) was addeddropwise to a solution of the product from Preparation 5 (370 mg) indichloromethane (4 ml) containing methyl acrylate (144 μl). Theresulting mixture was stirred for 4 hours, whereafter further methylacrylate (144 μl) was added and stirring was continued overnight. Thereaction mixture was then worked up and the product was purified bychromatography to give the title compound (345 mg): IR (CDCl₃) υ_(max)1600, 1720 cm⁻¹; NMR (CDCl₃) δ 0.8 (s, 18-H's), 3.6 (s, OCH's), 5.1-5.4(bs, 16-H's), 6.4, 6.58 (s, 1,4-H's).

b)2-Methoxy-3-triisopropylsilyloxy-19-nor-chol-1,3,5(10),16-tetraen-24-ol[Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=OCH₃, L=OH, Y^(a)=(CH₂)₃, Δ16double bond]

Lithium aluminium hydride (1 ml of a 1 M solution in ether) was addeddropwise to a solution of the ester from (a) above (265 mg) in ether (5ml), whereafter the reaction mixture was stirred for 30 minutes, dilutedwith ether and quenched with wet sodium sulphate, giving crude titlecompound (248 mg): IR (CDCl₃) υ_(max) 1600, 3380-3660 cm⁻¹; NMR (CDCl₃)δ 0.8 (s, 18-H's), 3.3-3.8 (b, HOCH's), 3.7 (s, OCH's), 5.1-5.4 (bs,16-H's), 6.4, 6.6 (s, 1,4-H's).

c)2-Methoxy-3-triisopropylsilyloxy-19-nor-chol-1,3,5(10),16-tetraen-24-ol,24-tosylate [Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=OCH₃,L=O,SO₂,C₆H₄,CH₃, Y^(a)=(CH₂)₃, Δ16 double bond]

A solution of the alcohol from (b) above (248 mg) in dichloromethane (4ml) containing tosyl chloride (290 mg) and pyridine (250 μl) was stirredovernight. Work up and purification by chromatography gave the titlecompound (245 mg): IR (CDCl₃) υ_(max) 1595 cm⁻¹; NMR (CDCl₃) δ 0.7 (s,18-H's), 2.4 (s, tosyl-Me), 3.8-4.1 (b, TsOCH's), 3.7 (s, OCH's),5.0-5.3 (bs, 16-H's), 6.4, 6.56 (s, 1,4-H's), 7.0-7.8 (ABq, tosylarH's).

d)2-Methoxy-3-triisopropylsilyloxy-19-nor-chol-1,3,5(10),16-tetraene-24-bromide[Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=OCH₃, L=Br, Y^(a)=(CH₂)₃, Δ16double bond]

The tosylate from (c) above (245 mg) was dissolved in dichloroethane (6ml) and acetonitrile (6 ml) containing lithium bromide (310 mg) and theresulting mixture was heated under reflux for 3 hours. The mixture wasworked up and the product was purified by chromatography to give thetitle compound (200 mg): IR (CDCl₃) υmax 1600 cm⁻¹; NMR (CDCl₃) δ 0.83(s, 18-H's), 3.2-3.5 (b, BrCH's), 3.73 (s, OCH's), 5.1-5.4 (bs, 16-H's),6.43, 6.56 (s, 1,4-H's).

e)2-Methoxy-3-triisopropylsilyloxy-20α-formyl-19-nor-pregn-1,3,5(10)-triene[Formula (IX): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=OCH₃, Y^(b)=valence bond]

This is prepared from the product of Preparation 5 according to theprocedures of Preparations 3(a), 3(b) and 4.

f)2-Methoxy-3-triisopropylsilyloxy-20α-bromomethyl-19-nor-pregn-1,3,5(10)-triene[Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=OCH₃, Y^(a)=CH₂, L=Br]

This is prepared from the product of Preparation 5 according to theprocedures of Preparations 3(a)-(d).

Preparation 7

a) 3-Triisopropylsilyloxy-19-nor-pregn-1,3,5(10), 6,8,17(20)Z-hexaene

3-Hydroxy-19-nor-androst-1,3,5(10),6,8 pentaen-17-one was subjected to aWittig reaction followed by silylation as in Preparation 5 to give thetitle compound: IR (CDCl₃) υ_(max) 1590, 1610 cm⁻¹; NMR (CDCl₃) δ 0.73(s, 18-H's), 1.73 (d, ═CH—CH's), 4.8-5.5 (q, ═CH—Me), 6.7, 8.0 (s, 1-,2-, 4-,6- and 7-H's).

b) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5 (10),6,8,16-hexaene-24-carboxylic acid methyl ester [Formula (VI): R³=α-CH₃,R⁴=(i-Pr)₃Si, R⁵=H, R9=CH3, Y=(CH₂)₂, Δ6, Δ8 and Δ16 double bonds]

The product from (a) above was subjected to an ene reaction as inPreparation 6(a) to give the title compound: IR (CDCl₃) υ_(max) 1590,1610, 1725 cm⁻¹; NMR (CDCl₃) δ 0.67 (s, 18-H's), 0.82 (d, 21-H's),2.9-3.5 (bm, 23-H's), 3.63 (s, COOCH's), 5.2-5.6 (bs, 16-H's), 6.7, 8.0(s, 1-, 2-, 4-, 6- and 7-H's).

c) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10), 6,8,16-hexaen-24-ol[Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, L=OH, Y^(a)=(CH₂)₃, Δ6, Δ8and Δ16 double bonds]

The product from (b) above was reacted as in Preparation 6(b) to givethe title compound: IR (CDCl₃) υ_(max) 1590, 1600, 3360-3660 cm⁻¹; NMR(CDCl₃) δ 0.66 (s, 18-H's), 0.82 (d, 21-H's), 3.4-3.9 (b, HOCH's),5.2-5.5 (bs, 16-H's), 6.8-8.0 (s, 1-, 2-, 4-, 6- and 7-H's)

d) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10), 6,8,16-tetraen-24-ol,24-tosylate [Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H,L=O,SO₂,C₆H₄,CH₃, Y^(a)=(CH₂)₃, Δ6, Δ8 and Δ16 double bonds]

The product from (c) above was reacted as in Preparation 6(c) to givethe title compound: IR (CDCl₃) υ_(max) 1590, 1610 cm⁻¹; NMR (CDCl₃) δ0.6 (s, 18-H's), 0.78 (d, 21-H's), 2.4 (s, tosyl-Me), 3.8-4.3 (b,TsOCH's), 5.2-5.5 (bs, 16-H's), 6.8-8.1 (m, 1-, 2-, 4- and tosyl arH's).

e) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10),6,8,16-hexaene-24-bromide [Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃, Si, R⁵=OCH₃,L=Br, Y^(a)=(CH₂)₃, Δ6, Δ8 and Δ16 double bonds]

This was prepared by reacting the tosylate from (d) above according tothe method of Preparation 6(d) to give the title compound: IR (CDCl₃)υ_(max) 1590, 1600 cm⁻¹; NMR (CDCl₃) δ 0.66 (s, 18-H's), 5.2-5.5 (bs,16-H's), 6.8-8.0 (m, 1-, 2-, 4-, 6- and 7-H's)

Preparation 8

a) 3-Tetrahydropyranyloxy-19-nor-pregn-1,3,5 (10),17(20)E-tetraene-21-carboxylic acid ethyl ester

A solution of estrone-3-tetrahydropyranyl ether (1.25 g, preparedaccording to J. Chem. Soc. Perkin, pp. 1282-1286, [1978]) in ethanol (18ml) containing diethyl ethoxycarbonylmethylphosphonate (2.65 ml) wastreated with sodium ethoxide (6.75 ml of a 21% solution in ethanol) andheated under reflux for 15 hours. After work up the product was purifiedby chromatography to afford the title compound (1.12 g): IR (CDCl₃)υ_(max) 1450-1600, 1645, 1695 cm⁻¹; NMR (CDCl₃) δ 0.8 (s, 18-H's), 3.55(m, six H's of THP), 4.05 (q, COOCH's), 5.25 (m, two H's of THP), 5.45(20-H), 6.7-7.05 (m, 1-, 2- and 4-H's).

b) 3-Tetrahydropyranyloxy-19-nor-pregn-1,3,5(10), 17(20)E-tetraen-21-ol

Lithium aluminium hydride (4.9 ml of a 1 M solution in ether) was addedto a solution of the ester from (a) above (1 g) in ether (4 ml). After 4hours the reaction was quenched with wet sodium sulphate, the reactionmixture was worked up and the solvent was removed to give the titlecompound (0.9 g): IR (CDCl₃) υ_(max) 1610, 3580 cm⁻¹; NMR (CDCl₃) δ 0.76(s, 18-H's), 3.35 (m, six H's of THP), 3.95 (d, 21-H's), 5.25 (m, twoH's of THP), 5.1 (20-H), 6.7-7.05 (m, 1-, 2- and 4-H's).

c) 3-Triisopropylsilyloxy-19-nor-pregn-1,3,5(10), 17 (20)E-tetraene

A solution of the alcohol from (b) above (0.9 g) in tetrahydrofuran (10ml) at 0° was treated with pyridinium sulphate (576 mg). The resultingmixture was stirred for 4 hours, whereafter lithium aluminium hydride(9.6 ml of a 1M solution in tetrahydrofuran) was added and stirring wascontinued for 1 hour at 0° and then at room temperature overnight. Thecrude product (0.7 g), containing a mixture of the 3-OH compound and the3-THP ether, was cleaved by storage overnight in acetone (15 ml)containing p-toluenesulphonic acid (150 mg of hydrate). The cleaved 3-OHproduct (700 mg) was silylated by treatment withchlorotriisopropylsilane (623 μl) in dichloromethane (3 ml) containingimidazole (720 mg) at room temperature overnight, and following work upgave the title compound (800 mg): IR (CDCl₃) υ_(max) 1610, 1600-1450(three bands) cm⁻¹; NMR (CDCl₃) δ 0.78 (s, 18-H's), 1.05-1.2 (silylH's), 1.50 (d, 21-H's), 5.0 (q, 20-H), 6.5-6.95 (m, 1-, 2- and 4-H's).

d)3-Triisopropylsilyloxy-20-epi-19-nor-chol-1,3,5(10),16,22-pentane-24-carboxylicacid methyl eater [Formula (VI): R³=β-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, R0=CH3,Y=CH═CH, Δ16 double bond]

A solution of the E-alkene from (c) above (800 mg) in benzene wastreated with diethyl aluminium chloride (3.19 ml) and methyl propiolate(0.415 ml) and stirred for 3 days. The reaction mixture was then workedup and the product was purified by chromatography to give the titlecompound: IR (CDCl₃) υ_(max) 1640, 1710 cm⁻¹; NMR (CDCl₃) δ 0.78 (s,18-H's), 3.5 (s, OCH's), 4.0 (by product), 5.2 (t, 16-H's), 6.5, 6.95(s, 1-, 2- and 4-H's).

e) 3-Triisopropylsilyloxy-20-epi-19-nor-chol-1,3,5(10),16-tetraen-24-ol[Formula (VII): R³=β-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, L=OH, Y^(a)=(CH₂)₃, Δ16double bond]

Treatment of the ester from (d) above (400 mg) with lithium aluminiumhydride according to the method of Preparation 6(b) (except with inverseaddition) and work up gave the title compound (360 mg, mixed with the22,23 unsaturated alcohol in a ratio of approximately 85:15): IR (CDCl₃)υ_(max) 1600, 3580 cm⁻¹; NMR (CDCl₃) δ 0.78 (s, 18-CH's), 3.5 (m,HOCH's), 3.7 (s, OCH's), 5.1-5.4 (bs, 16-H's), 6.4, 6.6 (s, 1-, 2- and4-H's).

f) 3-Triisopropylsilyloxy-20-epi-19-nor-chol-1,3,5(10),16-tetraen-24-ol,24-tosylate [Formula (VII): R³=β-CH₃, R⁴=(i-Pr)₃Si, R⁵=H,L=O,SO₂,C₆H₄,CH₃, Y^(a)=(CH₂)₃, Δ16 double bond]

The alcohol from (e) above (360 mg) was tosylated as in Preparation6(c). The desired product was separated from the “unreacted” 22,23unsaturated alcohol by chromatography to give the title compound (380mg): NMR (CDCl₃) δ 0.78 (s, 18-H's), 2.4 (s, tosyl-Me), 3.95 (t,TsOCH's), 5.15 (bs, 16-H's), 6.4, 6.95 (s, 1,4-H's), 7.2-7.7 (ABq, tosylarH's).

g)3-Triisopropylsilyloxy-20-epi-19-nor-chol-1,3,5(10),16-tetraene-24-bromide[Formula (VII): R³=β-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, L=Br, Y^(a)=(CH₂)₃, Δ16double bond]

The tosylate from (f) above (500 mg) was dissolved in a mixture ofdichloroethane (13 ml) and acetonitrile (13 ml) containing lithiumbromide (700 mg) and the resulting mixture was heated under reflux for3.5 hours. The mixture was then worked up and the product was purifiedby chromatography to give the title compound (350 mg): NMR (CDCl₃) δ0.78 (s, 18-H's), 3.35 (b, BrCH's), 5.25 (bs, 16-H's), 6.5, 6.95 (s,1,4-H's).

h) 3-Triisopropylsilyloxy-20β-formyl-19-nor-pregn-1,3,5(10)-triene[Formula (IX): R³=β-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y^(b)=valence bond]

This is prepared from the product of Preparation 8(c) according to theprocedures of Preparations 3 (a), 3 (b) and 4.

i) 3-Triisopropylsilyloxy-20β-bromomethyl-19-nor-pregna-1,3,5(10)-triene[Formula (VII): R³=β-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y^(a)=CH₂, L=BR]

This is prepared from the product of Preparation 8(c) according to theprocedures of Preparations 3(a)-(d)

Preparation 9

a) 3-Triisopropylsilyloxy-19-nor-pregn-1,3,5(10), 8,17(20)Z-pentane

3-Hydroxy-19-nor-androst-1,3,5(10),8-tetraen-17-one was subjected to aWittig reaction followed by silyation as in Preparation 5 to give thetitle compound: IR (CDCl₃) υ_(max) 1600 cm⁻¹; NMR (CDCl₃) δ 0.8 (s,18-H's), 4.8-5.4 (b, ═CH—Me, 8H), 6.7-7.3 (m, 1-, 2- and 4-H's).

b)3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10),6.16-pentaene-24-carboxylicacid methyl ester [Formula (VI): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, R⁹=CH₃,Y=(CH₂)₂, Δ6 and Δ16 double bonds]

The product from (a) above was subjected to an ene reaction as inPreparation 6(a) to give the title compound: IR (CDCl₃) υ_(max) 1590,1610, 1725 cm⁻¹; NMR (CDCl₃) δ 0.67 (s, 18-CH's), 3.8-4.3 (q, COOCH's),5.2-5.6 (bs, 16-H's), 6.8-8.0 (s, 1-, 2-, 4- and 6-H's).

c) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10), 6,16-pentaen-24-ol[Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, L=OH, Y^(a)=(CH₂)₃, Δ16and Δ16 double bonds]

Reaction of the product from (b) above as in Preparation 6(b) gave thetitle compound: IR (CDCl₃) υ_(max) 1595, 1620, 3300-3640 cm⁻¹; NMR(CDCl₃) δ 0.7 (s, 18-CH's), 3.3-3.8 (b, HOCH's), 5.1-5.5 (b, 16-H's),6.8-7.9 (s, 1-, 2-, 4- and 6-H's).

d) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10),6,16-pentaen-24-ol,24-tosylate [Formula (VII): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H,L=O,SO₂,C₆H₄,CH₃, Y^(a)=(CH₂)₃, Δ6 and Δ16 double bonds]

Reaction of the product from (c) above as in Preparation 6(c) gave thetitle compound: IR (CDCl₃) υ_(max) 1590,1625 cm⁻¹; NMR (CDCl₃) δ 0.6 (s,18-CH's), 2.37 (s, tosyl-Me), 3.7-4.2 (b, TsOCH's), 5.1-5.5 (b, 16-H's),6.7-7.9 (m, 1-, 2-, 4-, 6- and tosyl arH's).

e) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10),6,16-pentaene-24-bromide[Formula (V): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, L=Br, Y^(a)=(CH₂)₃, Δ6 andΔ16 double bonds]

Reaction of the tosylate from (d) above according to the method ofPreparation 6(d) gave the title compound: IR (CDCl₃) υ_(max) 1585, 1610cm⁻¹; NMR (CDCl₃) δ 0.63 (s, 18-H's), 5.1-5.5 (b, 16-H's), 6.7-7.9 (m,1-, 2-, 4- and 6-H's).

EXAMPLE 1 a)3-Triisopropylsilyloxy-23,23a-bishomo-19-nor-chol-1,3,5(10)16-tetraene-24-nitrile[Formula (II): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y=(CH₂)₄, Δ16 double bond]

A solution of acetonitrile (0.16 ml) in tetrahydrofuran (1.5 ml) wasadded dropwise at −78° to a solution of butyl lithium in hexane (3 mM in1.9 ml) and the reaction mixture was stirred for 50 minutes. The bromidefrom Preparation 1(c) (150 mg) in tetrahydrofuran (3 ml+1 ml wash) wasadded and the mixture was stirred for a further hour then warmed to −30°for an hour. TLC indicated the absence of starting material, so themixture was cooled to −78° and treated with ammonium chloride. Theproduct was extracted into ether and worked up to afford the titlecompound (85 mg): IR υ_(max) 2250, 1620 cm⁻¹; NMR (CDCl₃) δ 0.96 (s,18-H's), 5.2 (bs, 16-H), 6.5 and 6.95 (m, 1-, 2- and 4-H's).

b)25-Amino-3-triisopropylsilyloxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=NH₂, Y=(CH₂)₄,Δ16 double bond]

Anhydrous cerous chloride was prepared by heating CeCl₃.7H₂O (2 g) invacuo (<0.1 mm Hg) first at 70° for 1 hour, then at 110° for 1 hour andfinally at 145° for 2½ hours. Thus-obtained anhydrous cerous chloride(256 mg) was heated in vacuo at 130° for 2 hours, cooled, then suspendedin tetrahydrofuran (3 ml); the resulting mixture was kept overnight withstirring. The suspension was cooled to −78° and then treated with methyllithium (0.86 ml of a 1.4 M solution in ether). The mixture was stirredfor 15 minutes at −78°, 15 minutes at 0°, then cooled to −78° and thenitrile from (a) above (84 mg) in tetrahydrofuran (2 ml+1 ml wash) wasadded dropwise. After a further hour at −78° (TLC control), ammoniumhydroxide was added and the mixture was warmed to room temperature andfiltered through Celite (methylene chloride wash). Removal of thesolvents gave the title compound (67 mg, isolated by chromatography): IRυ_(max) 1620 cm⁻¹; NMR (CDCl₃) δ 0.96 (s, 18-H's), 0.99 (21-H's), 1.25(25-H's), 5.2 (bs, 16-H), 6.5 and 6.95 (m, 1-, 2- and 4-H's).

c)25-Acetylamino-3-triisopropylsilyloxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=NH(COCH₃),Y=—(CH₂)₄, Δ16 double bond]

The amine from (b) above (67 mg) in dichloromethane (2 ml) containingpyridine (0.475 ml) and acetic anhydride (0.475 ml) was stirred for 4hours, whereafter the mixture was diluted with dichloromethane, treatedwith aqueous sodium bicarbonate, and stirred overnight. Work up affordedthe title compound (70 mg, isolated by preparative TLC): IR υ_(max)1690, 1620, 1600-1450 cm⁻¹; NMR (CDCl₃) δ 0.96 (s, 18-H's), 0.99(21-H's), 1.25 (25-H's), 1.9 (s, COCH's) 5.0 (s, NH), 5.15 (bs, 16-H),6.5 and 6.95 (m, 1-, 2- and 4-H's).

d) 25-Acetylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=R⁵=H, X=NH(COCH₃), Y=(CH₂)₄, Δ16double bond]

The silyl compound from (c) above (70 mg) in tetrahydrofuran (1.5 ml)was desilylated by treatment overnight with tetrabutylammonium fluoride(1.3 ml of a 1 M solution in tetrahydrofuran). The crude product (40 mg)was purified by TLC to give the title compound (27 mg): NMR (CDCl₃) δ0.76 (s, 18-H's), 0.95, 1.0 (21-H's), 1.3 (25-H's), 1.9 (s, COCH's),5.1-5.3 (m, NH, 16-H), 6.5 and 6.95 (m, 1-, 2- and 4-H's).

e) 25-Ethylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=NH(CH₂CH₃),Y=(CH₂)₄, Δ16 double bond]

The title compound is prepared by reduction of the product of (c) abovewith lithium aluminium hydride in tetrahydrofuran for 3 hours followedby removal of the silyl group according to step (d) above.

f) 25-Methylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=NH(CH₃),Y=(CH₂)₄, Δ16 double bond]and25-dimethylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=N(CH₃)₂,Y=(CH₂)₄, Δ16 double bond]

The title compounds are prepared by methylation with methyliodide/calcium oxide of the product from (c) above and separation of theproducts by chromatography followed by desilylation as in step (d)above.

g)25-(N-Ethyl-N-methylamino)-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=N(CH₃)(CH₂CH₃),Y=(CH₂)₄, Δ16 double bond]

The title compound is prepared by methylation of the N-ethyl 3-silylether compound prepared as an intermediate in step (e) above, followedby desilylation according to the procedure in step (d) above.

h) 25-Acetylamino-3-methoxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=CH₃, R⁵=H, X=NH(COCH₃), Y=(CH₂)₄,Δ16 double bond]

The title compound is prepared by methylation of the product of Example1(d) with sodium hydride/methyl iodide.

i) 25-Acetylamino-3-ethoxy-24-homo-19-nor-cholest-1,3,5(10), 16-tetraen[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=CH₃CH₂, R⁵=H, X=NH(COCH₃),Y=(CH₂)₄, Δ16 double bond]

The title compound is prepared as in step (h) above using ethyl iodidein place of methyl iodide.

j) 25-Acetylamino-3-ethoxy-24-homo-19-nor-cholest-1,3,5(10), 16-tetraen[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(CH₃)₂CHCH₂, R⁵=H, X=NH(COCH₃),Y=(CH₂)₄, Δ16 double bond]

The title compound is prepared as in step (h) above using isobutylbromide in place of methyl iodide.

Alternatively, analogues of any of the compounds in the Examples havingR⁴=lower alkyl may be prepared by starting from the correspondingestrone 3-ether and following the remaining steps without modification.

k) 25-Benzamido-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=R⁵=H, X=NH(COC₃H₅), Y=(CH₂)₄, Δ16double bond]

The title compound is prepared by substituting benzoyl chloride foracetic anhydride in step (c) above and desilylating the resultingproduct as in step (d) above.

l)25-Phenylacetylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=R⁵=H, X=NH(CO,CH₂,C₆H₅), Y=(CH₂)₄,Δ16 double bond]

The title compound is prepared by substituting phenylacetyl chloride foracetic anhydride in step (c) above and desilylating the resultingproduct as in step (d) above.

EXAMPLE 2 a)3-Triisopropylsilyloxy-23,23a-bishomo-19-nor-chol-1,3,5(10)-tetraene-24-nitrile[Formula (II): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y=(CH₂)₄]

The bromide from Preparation 2(c) (130 mg) was treated withα-lithio-acetonitrile as in Example 1 (a) to give the title compound(140 mg crude, 65 mg after chromatography): IR υ_(max) 2250 cm⁻¹; NMR(CDCl₃) δ 0.80 (s, 18-H's), 6.5 and 6.95 (m, 1-, 2- and 4-H's).

b)25-Amino-3-triisopropylsilyloxy-24-homo-19-nor-cholest-1,3,5(10)-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, X=NH₂, Y=(CH₂)₄]

The nitrile from (a) above (65 mg) was treated with methyl cerouschloride as in Example 1 (b) to give the title compound (58 mg): NMR(CDCl₃) δ 0.80 (s, 18-H's), 1.3 (s, 25-H's), 6.5 and 6.95 (m, 1-, 2- and4-H's).

c)25-Acetylamino-3-triisopropylsilyloxy-24-homo-19-nor-cholest-1,3,5(10)-triene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=NH(COCH₃),Y=(CH₂)₄]

The amine from (b) above (58 mg) was acetylated as in Example 1(c) togive the title compound (57 mg): NMR (CDCl₃) δ 0.80 (s, 18-H's), 1.3 (s,25-H's), 1.9 (s, COCH's), 5.1 (s, NH), 6.5 and 6.95 (m, 1-, 2- and4-H's).

d) 25-Acetylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10)-triene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=H, R⁵=H, X=NH(COCH₃), Y=(CH₂)₄]

The silyl ether from (c) above (57 mg) was desilylated as in Example 1(d) to give the title compound (51 mg crude, 15 mg purified by TLC): NMR(CDCl₃) δ 0.80 (s, 18-H's), 1.3 (s, 25-H's), 1.9 (s, COCH's), 5.0-5.15(s, NH), 6.5 and 6.95 (m, 1-, 2- and 4-H's).

EXAMPLE 3 a)3-Triisopropylsilyloxy-19,26,27-trisnor-cholest-1,3,5(10)-trien-24-one[Formula (V): R¹=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y=(CH₂)₂]

Butyl lithium (0.94 ml, 1.5 mM) was added dropwise to1-triphenylphosphoranylidene-2-propanone (477 mg) in tetrahydrofuran (12ml) at −78° and the mixture was stirred for 30 minutes. The bromide fromPreparation 3(d) above (260 mg) in tetrahydrofuran (3 ml) was addeddropwise at −78° and the reaction mixture was stirred for 30 minutes,allowed to warm to 0° and then stirred for a further 3 hours. Afterstorage overnight at room temperature the solvent was removed and theresidue was dissolved in ethanol (15 ml) and water (6 ml) and heatedunder reflux overnight. The crude product, which had undergone in situdesilylation, was purified by chromatography to give the 3-OH analogueof the title compound (160 mg): IR (CDCl₃) υ_(max) 1600, 1700, 3160-3460cm⁻¹; NMR (CDCl₃) δ 0.67 (s, 18-H's), 2.13 (s, 25-H's), 6.3-7.3 (m, 1-,2- and 4-H's).

This product was silylated by treatment with triisopropylsilyl chloride(130 mg) and imadazole (122 mg) in dichloromethane (1 ml) and purifiedby chromatography to give the title compound: IR (CDCl₃) υ_(max) 1600,1700 cm⁻¹; NMR (CDCl₃) δ 0.67 (s, 18-H's), 2.07 (s, 25-H's), 6.3-7.2 (m,1-, 2- and 4-H's).

b)3-Triisopropylsilyloxy-24-propargyl-19,26,27-trisnor-cholest-1,3,5(10)-trien-24-ol[Formula (I): R¹=CH₃, R²=CH₂C≡CH, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=OH,Y=(CH₂)₂]

A reagent solution was prepared as follows: propargyl bromide (2.53 g,80% by weight in toluene) in ether (18 ml) was added dropwise toaluminium powder (900 mg) and powdered mercuric chloride (45 mg) inether (4 ml) and the mixture was refluxed overnight. The total volume ofthe resulting solution was 24 ml. A portion of this reagent (0.8 ml) wasadded dropwise to a solution of the ketone from (a) above (60 mg) intetrahydrofuran (1 ml), and the resulting mixture was stirred at roomtemperature for 15 minutes. Ether and wet sodium sulphate were thenadded to coagulate the aluminium compounds, whereafter the solution wasfiltered and the solvents were removed to give the title compound (55mg): IR (CDCl₃) υ_(max) 1600, 3280 cm⁻¹; NMR (CDCl₃) δ 0.7 (s, 18-H's),6.3-7.2 (m, 1-, 2- and 4-H's).

c) 3,24-Dihydroxy-24-propargyl-19-26,27-trisnor-cholest-1,3,5(10)-triene[Formula (I): R¹=CH₃, R²=CH₂C≡CH, R³=α-CH₃, R⁴=R⁵=H, X=OH, Y=(CH₂)₂]

The product from (b) above (55 mg) was desilylated as in Example 1(d) togive the title compound (38 mg): IR (CDCl₃) υ_(max) 1590, 1600, 3300,3310-3620 cm⁻¹; NMR (CDCl₃) δ 0.7 (s, 18-H's), 1.2 (9, C≡CH), 4.6-5.1(bs, OH), 6.3-7.2 (m, 1-, 2- and 4-H's).

d)2-Methoxy-3,24-dihydroxy-24-propargyl-19,26,27-trisnor-cholesta-1,3,5(10)-triene[Formula (I): R¹=CH₃, R²=CH₂C≡CH, R³=α-CH₃, R⁴=H, R⁵=OCH₃, X=OH,Y=(CH₂)₂]

This is prepared from the bromide of Preparation 6(d) by the proceduresof steps (a)-(d) above.

e)3,24-Dihydroxy-20-epi-24-propargyl-19,26,27-trisnor-cholest-1,3,5(10)-triene[Formula (I): R¹=CH₃, R²=CH₂C≡CH, R³=β-CH₃, R⁴=R⁵=H, X=OH, Y=(CH₂)₂]

This is prepared from the bromide of Preparation 8(i) by the proceduresof steps (a)-(d) above.

EXAMPLE 4 a) 3-Triisopropylsilyloxy-19-nor-chol-1,3,5(10),22-tetraene-24-carboxylic acid ethyl ester [Formula (VI): R³=α-CH₃,R⁴=(i-Pr)₃Si, R⁵=H, R⁹=CH₂CH₃, Y=CH═CH]

The aldehyde from Preparation 4 (120 mg) and carboethoxymethylenetriphenylphosphorane (4 equivalents) in dimethylsulphoxide were stirredat 105° for 5 hours, whereafter the mixture was cooled, diluted withethyl acetate and washed, and the solvents were removed. The resultingproduct was purified by chromatography to give the title compound (95mg): IR (CDCl₃) υ_(max) 1595, 1635, 1695 cm⁻¹; NMR (CDCl₃) δ 0.7 (s,18-H's), 3.8-4.3 (q, —O—CH of ethyl), 5.3-5.8, 7.2-7.7 (m, side chain—CH═CH's), 6.3-7.2 (m, 1-, 2- and 4-H's).

b)3-Triisopropylsilyloxy-24,24-bispropargyl-19-nor-chol-1,3,5(10),22-tetraen-24-ol[Formula (I): R¹=R²=CH₂C≡CH, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=OH,Y=CH═CH]

Propargyl aluminum reagent as prepared as in Example 3(b) (0.7 ml, 5equivalents) was added dropwise to the ethyl ester from (a) above (55mg) in tetrahydrofuran (1 ml). The resulting mixture was stirred for 1hour and then worked up. The product was purified by PTLC to give thetitle compound (45 mg): IR (CDCl₃) υ_(max) 1600, 3280, 3500-3600 cm⁻¹;NMR (CDCl₃) δ 0.7 (s, 18-H's), 5.4-5.7 (m, side chain —CH═CH's), 6.3-7.3(m, 1-, 2- and 4-H's).

c) 3,24-Dihydroxy-24,24-bispropargyl-19-nor-chol-1,3,5(10),22-tetraene[Formula (I): R¹=R²=CH₂C≡CH, R³=α-CH₃, R⁴=R⁵=H, X=OH, Y=CH═CH

The silyl ether from (b) above (45 mg) was desilylated by treatment withtetrabutylammonium fluoride (0.3 ml) in tetrahydrofuran (0.3 ml) at roomtemperature overnight. The product was purified by PTLC to give thetitle compound (25 mg): IR (CDCl₃) υ_(max) 1580, 1600, 3280, 3520-3620cm⁻¹; NMR (CDCl₃) δ 0.71 (s, 18-H's), 5.4-5.7 (bm, side chain —CH═CH's),6.3-7.3 (m, 1-, 2- and 4-H's).

d)2-Methoxy-3,24-dihydroxy-24,24-bispropargyl-19-nor-chol-1,3,5(10),22-tetraene[Formula (I): R¹=R²=CH₂C≡CH, R³=α-CH₃, R⁴=H, R⁵=OCH₃, X=OH, Y=Ch═CH]

This is prepared from the product of Preparation 6(e) by following theprocedures of steps (a)-(c) above.

e)3,24-Dihydroxy-20-epi-24,24-bispropargyl-19-nor-chol-1,3,5(10),22-tetraene[Formula (I): R¹=R²=CH₂C≡CH, R³=β-CH₃, R⁴=R⁵=H, X=OH, Y=CH═CH]

This is prepared from the product of Preparation 8(h) by following theprocedures of steps (a)-(c) above.

EXAMPLE 5 a)3-Hydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): R¹=R²=CH₂CH₃, R³=α-CH₃, R⁴=R⁵=H, X=NH₂, Y=CH₂—C≡C]

Butyl lithium (3.8 ml, 6.1 mmol) was added dropwise to a solution of1,1-diethylpropargylamine (800 mg) in hexane (20 ml) at 0°. Theresulting mixture was stirred for 30 minutes, brought to roomtemperature, stirred for a further 1.5 hours, and then cooled to 0°. Asolution of the 20-bromomethyl compound from Preparation 3(d) (300 mg)in hexane (4 ml) was added dropwise, whereafter the solution was stirredfor 30 minutes, warmed to 40° and then stirred for 24 hours. Thereaction was quenched with ammonium chloride and the product wasextracted into ether. The extract was washed, dried and purified bychromatography to give the title compound (110 mg): IR (CDCl₃) υ_(max)1580, 1600, 3000-3640 cm⁻¹; NMR (CDCl₃) δ 0.7 (s, 18-H's), 6.3-7.3 (m,1-, 2- and 4-H's).

b)2-Methoxy-3-hydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): R¹=R²=CH₂CH₃, R³=α-CH₃, R⁴=H, R⁵=OCH₃, X=NH₂, Y=CH₂C≡C]

This is prepared from the product of Preparation 6(f) by following theprocedure of step (a) above.

c)3-Hydroxy-20-epi-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): =R²=CH₂CH₃, R³=β-CH₃, R⁴=R⁵=H, X=NH₂, Y=CH₂C≡C

This is prepared from the product of Preparation 8(i) by following theprocedure of step (a) above.

EXAMPLE 6 a)3-Hydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-triene[Formula (I): R¹=R²=—CH₂CH₃, R³=α-CH₃, R⁴=R⁵H, X=NH₂, Y=(CH₂)₃]

A solution of the amine from Example 5(a) (70 mg) in ethanol (3.5 ml)containing 5% platinum on carbon (15 mg) was stirred overnight underhydrogen. The resulting mixture was filtered, the solvent was removedfrom the filtrate, and the product was purified by PTLC to give thetitle compound (18 mg): IR (CDCl₃) υ_(max) 1580, 1600, 3000-3640 cm⁻¹;NMR (CDCl₃) δ 0.67 (s, 18-H's), 6.3-7.3 (m, 1-, 2- and 4-H's).

b)2-Methoxy-3-hydroxy-25-amino-26,27-bishomo-19-nor-cholesta-1,3,5(10)-triene[Formula (I): R¹=R²=CH₂CH₃, R³=α-CH₃, R⁴=H, R⁵=OCH₃, X=NH₂, Y=(CH₂)₃]

This is prepared from the product of Example 5(b) by following theprocedure of step (a) above.

c)3-Hydroxy-20-epi-25-amino-26,26-bishomo-19-nor-cholesta-1,3,5(10)-triene[Formula (I): R¹=R²=CH₂CH₃, R³=β-CH₃, R⁴=R⁵=H, X=NH₂, Y=(CH₂)₃]

This is prepared from the product of Example 5(c) by following theprocedure of step (a) above.

EXAMPLE 7 a)3-Hydroxy-25-acetylamino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): R¹=R²=CH₂CH₃, R³=α-CH₃, R⁴=R⁵=H, X=NH(COCH₃), Y=CH₂—C≡C]

The product from Example 5(a) (10 mg) was treated at room temperatureovernight with acetic anhydride (12 mg) in methanol (0.1 ml) containingproton sponge (12 mg). The reaction mixture was worked up and theproduct was purified by PTLC to give the title compound (10 mg): NMR(CDCl₃) δ 0.67 (s, 18-H's),1.86 (s, NHCOCH's), 6.3-7.3 (m, 1-, 2- and4-H's).

b)2-Methoxy-3-hydroxy-25-acetylamino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): R¹=R²=CH₂CH₃, R³=α-CH₃, R⁴=H, R⁵=OCH₃, X=NH(COCH₃),Y=CH₂—C≡C]

This is prepared from the product of Example 5(b) by following theprocedure of step (a) above.

c)3-Hydroxy-20-epi-25-acetylamino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): R¹=R²=CH₂CH₃, R³=α-CH₃, R⁴=R⁵=H, X=NH(COCH₃), Y=CH₂—C≡C]

This is prepared from the product of Example 5(c) following theprocedure of step (a) above.

EXAMPLE 8 a)3-Triisopropylsilyloxy-22-hydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): R¹=R²=CH₂CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=NH₂,Y=CH(OH)—C≡C]

The 20-formyl compound from Preparation 4 (200 mg) in tetrahydrofuran (1ml) was added at −78° to a solution of the anion prepared from1,1-diethylpropargylamine (400 mg) and butyl lithium (1.9 ml, 3 mmol) asin Example 5(a). The resulting mixture was stirred at −78° for 30minutes, quenched with ammonium acetate, brought to room temperature andworked up. The product was purified by chromatography to give the titlecompound (150 mg): NMR (CDCl₃) δ 0.7 (s, 18-H's), 4.3-4.6 (bs, 22-HOCH),6.3-7.3 (m, 1-, 2- and 4-H's).

b)3,22-Dihydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): R¹=R²=CH₂CH₃, R³=αCH₃, R⁴=R⁵=H, X=NH₂, Y=CH(OH)—C≡C]

The silyl compound from (a) above (50 mg) was desilylated by treatmentwith tetrabutylammonium fluoride (0.3 ml) in tetrahydrofuran (0.3 ml)overnight at room temperature. The resulting mixture was worked up andthe product was purified by PTLC to give the title compound: NMR (CDCl₃)δ 0.7 (s, 18-H's), 4.3-4.6 (bs, 22-HOCH), 6.3-7.3 (m, 1-, 2- and 4-H's).

c)2-Methoxy-3,22-dihydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): R¹=R²=CH₂CH₃, R³=α-CH₃, R⁴=H, R⁵=OCH₃, X=NH₂,Y=CH(OH)—C≡C]

This is prepared from the product of Preparation 6(e) following theprocedures of steps (a) and (b) above.

d)3,22-Dihydroxy-20-epi-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): R¹=R²=CH₂CH₃, =R³=β-CH₃, R⁴=R⁵=H, X=NH₂, Y=CH(OH)—C≡C]

This is prepared from the product of Preparation 8(h) following theprocedures of steps (a) and (b) above.

EXAMPLE 9 a)2-Methoxy-3-triisopropylsilyloxy-23,23a-bishomo-19-nor-chol-1,3,5(10),16-tetraene-24-nitrile[Formula (II): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=OCH₃, Y=(CH₂)₄, Δ16 doublebond]

A solution of α-lithio acetonitrile was prepared as follows:acetonitrile (0.32 ml) in tetrahydrofuran (2 ml) was added dropwise at−78° to a solution of butyl lithium (3.75 ml of a 1.6 M solution inhexane) in tetrahydrofuran (4 ml) and the solution stirred for 50minutes. All but a sixth of the solution (ca 1 mmol) was discarded,whereafter the bromide from Preparation 6(d) (200 mg) in tetrahydrofuran(2 ml) was added dropwise while maintaining the temperature at −78°. Theresulting mixture was stirred for 1 hour, allowed to warm to −30°,stirred for a further hour, cooled back to −78°, quenched with ammoniumchloride, and worked up. The product was purified by chromatography togive the title compound (145 mg): IR (CDCl₃) υ_(max) 1600, 2240 cm⁻¹;NMR (CDCl₃) δ 0.8 (s, 18-H's), 3.7 (s, OCH's), 5.0-5.3 (bs, 16-H's),6.34, 6.6 (s, 1,4-H's).

b)2-Methoxy-3-triisopropylsilyloxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=OCH₃, X=NH₂,Y=(CH₂)₄, Δ16 double bond]

Cerium chloride (384 mg, 1.56 mmol, previously dried at <0.5 mm and 140°for 3 hours) was suspended in tetrahydrofuran (4 ml). This mixture wasstirred overnight and then cooled to −78°, whereafter methyl lithium(1.9 mmol, 1.34 ml of a 1.4 M solution in ether) was added dropwise andthe mixture was stirred for 15 minutes at −78°, warmed to 0°, stirredfor 15 minutes and cooled back to −78°. The nitrile from (a) above (145mg) in tetrahydrofuran (2 ml) was then added dropwise, and the mixturewas stirred for 1.5 hours and then quenched with aqueous ammoniumhydroxide. Following work up, removal of the solvent gave the titlecompound (145 mg): IR (CDCl₃) υ_(max) 1600, 3100-3700 cm⁻¹; NMR (CDCl₃)δ 0.77 (s, 18-H's), 1.3 (s, 26,27-H's), 3.67 (s, OCH's), 5.0-5.3 (bs,16-H's), 6.4, 6.58 (s, 1,4-H's).

c)2-Methoxy-3-triisopropylsilyloxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=OCH₃, X=NH(COCH₃),Y=(CH₂)₄, Δ16 double bond]

Acetylation of the amine from (b) above (85 mg) with acetic anhydride(0.425 ml) and pyridine (0.425 ml) in dichloromethane (2 ml) overnightat room temperature gave the title compound (65 mg, purified by PTLC):IR (CDCl₃) υ_(max) 1600, 1710, 3420 cm⁻¹; NMR (CDCl₃) δ 0.77 (s,18-H's), 1.88 (s, COCH₃), 3.7 (s, OCH's), 4.7-5.3 (b, NH′, 16-H's),6.43, 6.6 (s, 1,4-H's).

d)2-Methoxy-3-hydroxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=H, R⁵=OCH₃, X=NH(COCH₃), Y=(CH₂)₄,Δ16 double bond]

The amide from (c) above (65 mg) was desilylated by treatment withtetrabutylammonium fluoride (0.3 ml) in tetrahydrofuran (0.3 ml) for 4hours, and the crude product was isolated by PTLC to give the titlecompound (45 mg): IR (CDCl₃) υ_(max) 1590, 1710, 3420, 3520 cm⁻¹; NMR(CDCl₃) δ 0.8 (s, 18-H's), 1.3 (s, 26,27-H's), 1.86 (s, COCH₃), 3.78 (s,OCH's), 4.9-5.3 (b, NH, 16H's), 5.3-5.6 (s, OH), 6.47, 6.63 (s,1,4-H's).

e)2-Methoxy-3-hydroxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=H, R⁵=OCH₃, X=NH₂, Y=(CH₂)₄, Δ16double bond]

The title compound is obtained by desilylation of the product from (b)above according to the procedure of step (d) above.

f)2-Methoxy-3-hydroxy-25-acetylamino-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α—CH₃, R⁴=H, R⁵=OCH₃, X=NH(COCH₃), Y=(CH₂)₃,Δ16 double bond]

This is prepared by substituting sodium cyanide for the anion in step(a) above and thereafter following the procedures of steps (b)-(d)above.

g) 2-Methoxy-3-hydroxy-25-amino-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=H, R⁵=OCH₃, X=NH₂, Y=(CH₂)₂, Δ16double bond]

This is prepared by substituting sodium cyanide for the anion in step(a) above and thereafter following the procedures of steps (b) and (d)above.

EXAMPLE 10 a)Triisopropylsilyloxy-23,23a-bishomo-19-nor-chol-1,3,5(10),6,8,16-hexaene-24-nitrile[Formula (II): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y=(CH₂)₄, Δ6, Δ8 and Δ16double bonds]

Reaction of the bromide from Preparation 7(e) according to the method ofExample 9(a) gave the title compound: IR (CDCl₃) υ_(max) 1590, 1610,2230 cm⁻¹; NMR (CDCl₃) δ 0.66 (s, 18-H's), 5.2-5.5 (bs, 16-H's), 6.8-8.0(m, 1-, 2-, 4-, 6- and 7-H's).

b)3-Triisopropylsilyloxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),6,8,16-hexaene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵H, X=NH₂, Y=(CH₂)₄,Δ6, Δ8 and Δ16 double bonds]

The title compound was prepared by reaction of the nitrile from (a)above as in Example 9(b).

c)3-Triisopropylsilyloxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),6,8,16-hexaene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=NH(COCH₃),Y=(CH₂)₄, Δ6, Δ8 and Δ16 double bonds]

Acetylation of the amine from (b) above as in Example 9(c) gave thetitle compound (45 mg): IR (CDCl₃) υ_(max) 1595, 1605, 1670, 3420 cm⁻¹;NMR (CDCl₃) δ 0.67 (s, 18-H's), 1.3 (s, 26,27-H's), 1.87 (s, COCH₃),4.7-5.1 (b, NH), 5.1-5.4 (b, 16-H) 6.7-8.0 (s, 1-, 2-, 4-, 6- and7-H's).

d)3-Hydroxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),6,8,16-hexaene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=R⁵=H, X=NH(COCH₃), Y=(CH₂)₄, Δ6,Δ8 and Δ16 double bonds]

The amide from (c) above (45 mg) was desilylated by treatment withtetrabutylammonium fluoride (0.25 ml) in tetrahydrofuran (0.25 ml) atroom temperature overnight to give the title compound (28 mg, isolatedby PTLC): IR (CDCl₃) υ_(max) 1590, 1610, 1650, 3440 cm⁻¹; NMR (CDCl₃) δ0.67 (s, 18-H's), 1.0 (d, 21-H's), 1.27 (s, 26,27-H's), 1.88 (s, COCH₃),4.8-5.4 (b, NH, 16-H), 6.7-8.0 (m, 1-, 2-, 4-, 6- and 7-H's).

e) 3-Hydroxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),6,8,16-hexaene[Formula (I) R¹=R²=CH₃, R³=α-CH₃, R⁴=R⁵=H, X=NH₂, Y=(CH₂)₄, Δ6, Δ8 andΔ16 double bonds]

The title compound is obtained by desilylation of the product from (b)above according to the procedure of (d) above.

EXAMPLE 11 a)3-Triisopropylsilyloxy-25-triethylsilyloxy-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=OSi(CH₂CH₃)₃,Y=CH₂C≡C]

Butyl lithium (2.5 ml, 4 mmol) was added dropwise to a solution of[(1,1-dimethyl-2-propynyl)oxy]triethylsilane (792 mg) in hexanecontaining hexamethylphosphoramide (0.8 ml) at 0°. The resulting mixturewas stirred for 30 minutes at that temperature and for a further 1.5hours at room temperature, and was then cooled again to 0°, whereafter asolution of the bromide from Preparation 3(d) (210 mg) in hexane (4 ml)was added dropwise. The mixture was stirred for 30 minutes at 0°, 2hours at room temperature, and overnight at 45° C. The reaction wasquenched with ammonium chloride and worked up. Chromatography gave amixture of the 25-desilylated analogue (15 mg, see below) and the titlecompound (210 mg): NMR (CDCl₃) δ 0.72 (s, 18-H's), 1.48 (s, 26,27-H's,some at 1.42 for the silylated compound), 6.3-7.3 (1-, 2- and 4-H's).

b) 3,25-Dihydroxy-19-nor-cholest-1,3,5(10)-trien-23-yne [Formula (I),R¹=R²=CH₃, R³=α-CH₃, R⁴=R⁵=H, X=OH, Y=CH₂C≡C]

The product from (a) above was desilylated as in Example 1(d) andpurified by PTLC to give the title compound (50 mg, insoluble anddifficult to manipulate): IR (CDCl₃) υ_(max) 1600, 3480 cm⁻¹.

c) 3,25-Dihydroxy-19-nor-cholest-1,3,5(10)-triene [Formula (I),R¹=R²=CH₃, R³=α-CH₃, R⁴=R⁵=H, X=OH, Y=(CH₂)₃]

A solution of the product from (b) above (40 mg) in ethyl acetate (16ml) containing palladium (5% on carbon, 10 mg) was stirred overnightunder hydrogen. The reaction mixture was worked up and the product waspurified by PTLC to give the title compound (28 mg): NMR (CDCl₃) δ 0.7(s, 18-H's), 1.18 (s, 26,27-H's), 6.2, 7.3 (m, 1-, 2- and 4-H's).

d) 2-Methoxy-3,25-dihydroxy-19-nor-cholest-1,3,5(10)-trien-23-yne[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=H, R⁵=OCH₃, X=OH, Y=CH₂C≡C]

This is prepared from the product of Preparation 6(f) by following theprocedures of the above steps (a) and (b).

e) 3,25-Dihydroxy-20-epi-19-nor-cholest-1,3,5(10)-trien-23-yne [Formula(I): R¹=R²=CH₃, R³=β-CH₃, R⁴=R⁵=H, X=OH, Y=CH₂C≡C]

This is prepared from the product of Preparation 8(i) by following theprocedures of the above steps (a) and (b).

f) 2-Methoxy-3,25-dihydroxy-19-nor-cholest-1,3,5(10)-triene [Formula(I): R¹=R²=CH₃, R³=α-CH₃, R⁴=H, R⁵=OCH₃, X=OH, Y=(CH₂)₃]

This is prepared by hydrogenation of the product from (d) above as instep (c) above.

g) 3,25-Dihydroxy-20-epi-19-nor-cholest-1,3,5(10)-triene [Formula (I):R¹=R²=CH₃, R³=β-CH₃, R⁴=R⁵=H, X=OH, Y=(CH₂)₃]

This is prepared by hydrogenation of the product from (e) above as instep (c) above.

EXAMPLE 12 a)3-Triisopropylsilyloxy-24,24a-bishomo-19-nor-chol-1,3,5(10),22,24(24a)pentaene-24b-carboxylicacid ethyl ester [Formula (VI): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, R⁹=CH₂CH₃,Y=CH═CH—CH═CH]

The aldehyde from Preparation 4(b) (150 mg) was stirred at 105° for 4hours in dimethylsulphoxide (3 ml) containing the ylid prepared bywashing a solution of ethyl-4-bromotrimethylphosphonium butenoate (364mg) in dichloromethane with 2N sodium hydroxide and removing thesolvents. The reaction mixture was worked up and the product waspurified to give the 3-OH analogue of the title compound (40 mg) and thetitle compound (100 mg): IR (CDCl₃) υ_(max) 1600, 1630, 1690 cm⁻¹; NMR(CDCl₃) δ 0.73 (s, 18-H's), 3.8-4.4 (q, —O—CH of ethyl), 5.3-5.8,6.3-7.7 (m, side chain —CH═CH's, 1-, 2- and 4-H's).

b)3-Triisopropylsilyloxy-25-hydroxy-24,24a-bishomo-19-nor-cholest-1,3,5(10),22,24(24a)-pentaene [Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si—, R⁵=H,X=OH, Y=CH═CH—CH═CH]

Methyl lithium (0.36 ml, 5 equivalents) was added dropwise to a solutionof the ester from (a) above (58 mg) in tetrahydrofuran (4 ml) at −45°,and the resulting mixture was stirred for 30 minutes, then quenched andworked up. The product was purified by PTLC to give the title compound(27 mg): IR (CDCl₃) υ_(max) 1596, 3650 cm⁻¹; NMR (CDCl₃) δ 0.7 (s,18-H's), 1.32 (s, 26,27-H's), 5.2-6.2 (22-, 23-, 24- and 24a-H's),6.2-7.4 (m, 1-, 2- and 4-H's).

c)3,25-Dihydroxy-24,24a-bishomo-19-nor-cholest-1,3,5(10),22,24(24a)-pentaene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=R⁵=H, X=OH, Y=CH═CH—CH═CH]

The silyl ether from (b) above (27 mg) was desilylated as in Example1(d) and purified by PTLC to give title compound (18 mg): NMR(CDCl₃/CD₃OH) δ 0.72 (s, 18-H's), 1.3 (s, 26,27-H's), 5.1-6.3 (22-, 23-,24- and 24a-H's), 6.3-7.4 (m, 1-, 2- and 4-H's).

EXAMPLE 13 a)3-Triisopropylsilyloxy-20-epi-23,23a-bishomo-19-nor-chol-1,3,5(10),16-tetraene-24-nitrile[Formula (II): R³=β-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y=(CH₂)₄, Δ16 double bond]

Treatment of the bromide from Preparation 8(g) (350 mg) with the lithiumsalt of acetonitrile according to the procedure of Example 3(a) gave thetitle compound: IR υ_(max) 2250, 1610, 1450-1600 (3 bands) cm⁻¹; NMR(CDCl₃) δ 0.78 (s, 18-H's), 5.2 (bs, 16-H), 6.5, 6.95 (m, 1-, 2- and4-H's).

b)25-Amino-3-triisopropylsilyloxy-20-epi-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=β-CH₃, R⁴=(i-Pr)₃Si—, R⁵=H, X=NH₂,Y=—(CH₂)₄, Δ16 double bond]

The nitrite from (a) above was treated with cerium chloride/methyllithium according to the procedure of Example 3(b) to give the titlecompound (100 mg): IR (CDCl₃) υ_(max) 1610, 1450-1600 (3 bands) cm⁻¹;NMR (CDCl₃) δ 0.78 (s, 18-H's), 1.2 (26,27-H's), 5.2 (bs, 16-H), 6.5,6.95 (m, 1-, 2- and 4-H's).

c)25-Amino-3-hydroxy-20-epi-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=β-CH₃, R⁴=R⁵=H, X=NH₂, Y=(CH₂)₄—, Δ16 doublebond]

The silyl ether from (b) above (40 mg) was desilyated as in Example 1(d)to give the title compound: IR (CDCl₃) υ_(max) 3600, 1615, 1450-1600 (2bands) cm⁻¹; NMR (CDCl₃) δ 0.78 (s, 18-H's), 1.05 (d, 21-H's), 1.2(26,27-H's), 3.9 (bs, 3H [exchanges with D₂O]—OH, NH's), 5.2 (bs, 16-H),6.5, 6.95 (m, 1-, 2- and 4-H's).

d)25-Acetylmino-3-triisopropylsilyoxy-20-epi-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=β-H₃, R⁴=(i-Pr)₃Si, R⁵=H, X=NH(COCH₃),Y=(CH₂)₄—, Δ16 double bond]

The silyl ether from (b) above (60 mg) was acetylated as in Example 3(c)to give the title compound: IR (CDCl₃) υ_(max) 3420, 1660, 1610,1450-1600 (2 bands) cm⁻¹; NMR (CDCl₃) δ 0.78 (s, 18-H's), 1.2(26,27-H's), 1.9 (bs, NH), 5.2 (bs, 16-H), 6.5, 6.95 (m, 1-, 2- and4-H's).

e)25-Acetylamino-3-hydroxy-20-epi-24-homo-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I); R¹=R²=CH₃, R³=β-CH₃, R⁴=R⁵=H, X=NH(COCH₃), Y=—(CH₂)₄—, Δ16double bond]

The silyl either from (d) above (60 mg) was desilyated as in Example1(d) to give the title compound (36 mg): IR υ_(max) 3420, 1610, 1665,1450-1600 (2 bands) cm⁻¹; NMR (CDCl₃) δ 0.78 (s, 18-H's), 1.2(26,27-H's), 1.9 (bs, NH), 5.2 (bs, 16-H), 6.5, 6.95 (m, 1-, 2- and4-H's).

f) 25-Amino-3-hydroxy-20-epi-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=β-CH₃, R⁴=R⁵=H, X=NH₂, Y=(CH₂)₃, Δ16 doublebond]

This is prepared by substituting sodium cyanide for the anion in step(a) above and thereafter following the procedures of steps (b) and (c)above.

g) 25-Acetylamino-3-hydroxy-20-epi-19-nor-cholest-1,3,5(10),16-tetraene[Formula (I): R¹=R²=CH₃, R³=β-CH₃, R⁴=R⁵=H, X=NH(COCH₃), Y=(CH₂)₃, Δ16double bond

This is prepared by substituting sodium cyanide for the anion in step(a) above and thereafter following the procedures of steps (b), (d) and(e) above.

EXAMPLE 14 a)3-Triisopropylsilyloxy-23,23a-bishomo-19-nor-chol-1,3,5(10),6,16-pentaen-24-nitrile[Formula (II): R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, Y=(CH₂)₄, Δ6 and Δ16 doublebonds]

Reaction of the bromide from Preparation 9(e) in accordance with theprocedure of Example 9(a) gave the title compound: IR (CDCl₃) υ_(max)1590, 1615, 2240 cm⁻¹; NMR (CDCl₃) δ 0.67 (s, 18-H's), 5.2-5.5 (b,16-H's), 6.7-8.0 (m, 1-, 2- and 4-H's).

b)3-Triisopropylsilyloxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),6,16-pentaene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=NH₃, Y=(CH₂)₄,Δ6 and Δ16 double bonds]

The title compound was prepared from the nitrile from (a) above as inExample 9(b).

c)3-Triisopropylsilyloxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),6,16-pentaene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=(i-Pr)₃Si, R⁵=H, X=NH(COCH₃),Y=(CH₂)₄, Δ6 and Δ16 double bonds]

Acetylation of the amine from (b) above as in Example 9(c) gave thetitle compound (60 mg): IR (CDCl₃) υ_(max) 1590, 1615, 1660, 3420 cm⁻¹;NMR (CDCl₃) δ 0.67 (s, 18-H's), 1.26 (s, 26,27-H's), 1.87 (s, COCH₃),4.9-5.2 (b, NH), 5.2-5.5 (b, 16-H), 6.7-9.0 (s, 1-, 2-, 4- and 6-H's).

d)3-Hydroxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),6,16-pentaene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=H, R⁵=H, X=NH(COCH₃), Y=(CH₂)₄, Δ6and Δ16 double bonds]

The amide from (c) above (50 mg) was desilyated by treatment withtetrabutylammonium fluoride (0.3 ml) in tetrahydrofuran (0.35 ml) atroom temperature for 4 hours to give the title compound (36 mg, isolatedby PTLC): IR (CDCl₃) υ_(max) 1590, 1610, 1650, 3440-3640 cm⁻¹; NMR(CDCl₃) δ 0.63 (s, 18-H's), 1.3 (s, 26,27-H's), 5.0-5.5 (b, NH, 16-H),6.7-8.0 (m, 1,2-H's).

e) 3-Hydroxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),6,16-pentaene[Formula (I): R¹=R²=CH₃, R³=α-CH₃, R⁴=H, R⁵=H, X=NH₂, Y=(CH₂)₄, Δ6 andΔ16 double bonds]

The title compound is obtained by desilyation of the product from step(b) above by the procedure of step (d) above.

1. Compounds of formula (I)

in which: R¹ and R², which may be the same or different, each representsa lower alkyl,alkenyl or alkynyl group; R³ represents a methyl grouphaving α- or β-configuration; R⁴ represents a hydrogen atom or anetherifying or esterifying group; R⁵ represents a hydrogen atom, ahydroxyl group or a lower alkoxy group; X represents a group OR⁴,wherein R⁴ is as defined above, or a group NR⁶R⁷ wherein R⁶ represents ahydrogen atom, an aliphatic or arallphatic organic group, or an acylgroup comprising an aliphatic, araliphatic or aryl organic group linkedto the nitrogen atom by way of a carbonyl group; and R⁷ is a hydrogenatom or a lower alkyl group; Y represents a lower alkylene, alkenyleneor alkynylene group optionally substituted by a hydroxyl, etherifiedhydroxyl or esterified hydroxyl group; and the dotted lines signify thatdouble bonds may be present at the 16(17)-position and/or either at the6(7)- and 8(9)-positions or at the 7(8)-position.
 2. Compounds offormula (I) as claimed in claim 1 wherein R¹ and R² are independentlyselected from C₁₋₆ alkyl groups and C₂₋₇ alkenyl and alkynyl groups. 3.Compounds of formula (I) as claimed in claim 2 wherein R¹ and R² arestraight chain groups.
 4. Compounds of formula (I) as claimed in claim 2wherein R¹ and R² are selected from methyl, ethyl and propargyl groups.5. Compounds of formula (I) as claimed in claim 1 wherein R⁴ a hydrogenatom, a silyl group, a C₁₋₆ alkyl group optionally interrupted by one ormore oxygen atoms or substituted by a lower cycloalkyl group, a cyclicether group, a C₁₋₆ alkanoyl group, an aroyl group, a C₁₋₆ alkanesulphonyl or halogenated methane sulphonyl group, or an arene sulphonylgroup.
 6. Compounds of formula (I) as claimed in claim 5 wherein R⁴ is ahydrogen atom.
 7. Compounds of formula (I) as claimed in claim 5 whereinR⁴ is a metabolically labile group or a lower alkyl group.
 8. Compoundsof formula (I) as claimed in claim 1 wherein R⁵ represents a hydrogenatom or a methoxy group.
 9. Compounds of formula (I) as claimed in claim1 wherein X represents a hydroxyl group or a group of formula NR⁶R⁷wherein: R⁶ is a C₁₋₆ alkyl group, C₆₋₁₂ carbocyclic aryl C₁₋₄ alkylgroup, C₁₋₆ alkanoyl group, C₆₋₁₂ carbocyclic aryl C₂₋₅ alkanoyl group,C₇₋₁₃ carbocyclic aroyl group or any of the preceding groups substitutedby one or more halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkanoyl, C₁₋₄alkylamino, di (C₁₋₄ alkyl)amino, nitro, carbamoyl or C₁₋₄ alkanoylaminosubstituents; and R⁷ is a hydrogen atom or a C1-6 alkyl group. 10.Compounds of formula (I) as claimed in claim 9 wherein X represents ahydroxyl, amino, methylamino, ethylamino, N-ethyl-N-methylamino,acetylamino, benzamido or phenylacetylamino group.
 11. Compounds offormula (I) as claimed in claim 1 wherein Y contains up to 7 carbonatoms and up to 3 multiple bonds.
 12. Compounds of formula (I) asclaimed in claim 11 wherein Y is a straight chain C₂₋₆ group. 13.Compounds of formula (I) as claimed in claim 1 wherein Y is substitutedby a hydroxyl, etherified hydroxyl or esterified hydroxyl grouppositioned α-, β- or γ- to the group —C(R¹)(R²), X or α- to any triplebond present in the group Y.
 14. Compounds as claimed in claim 11wherein Y is selected from ethylene, trimethylene, tetramethylene,vinylene, buta-1,3-dienylene, prop-2-ynylene and1-hydroxyprop-2-ynylene.
 15. Compounds of formula (I) as claimed inclaim 1 wherein: R¹ and R², which may be the same or different, eachrepresents a lower alkyl group; R⁵ represents a hydrogen atom; and Xrepresents a group NR⁶R⁷ wherein R⁷ is hydrogen.
 16. The compounds:25-acetylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;25-ethylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;25-methylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;25-dimethylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;25-(N-ethyl-N-methylamino)-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;25-acetylamino-3-methoxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;25-acetylamino-3-ethoxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;25-acetylamino-3-isobutoxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;25-benzamido-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;25-phenylacetylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;25-acetylamino-3-hydroxy-24-homo-19-nor-cholest-1,3,5(10)-triene;3,24-dihydroxy-24-propargyl-19-26,27-trisnor-cholest-1,3,5(10)-triene;2-methoxy-3,24-dihydroxy-24-propargyl-19,26,27-trisnor-cholesta-1,3,5(10)-triene;3,24-dihydroxy-20-epi-24-propargyl-19,26,27-trisnor-cholest-1,3,5(10)-triene;3,24-dihydroxy-24,24-bispropargyl-19-nor-chol-1,3,5(10),22-tetraene;2-methoxy-3,24-dihydroxy-24,24-bispropargyl-19-nor-chol-1,3,5(10),22-tetraene;3,24-dihydroxy-20-epi-24,24-bispropargyl-19-nor-chol-1,3,5(10),22-tetraene;3-hydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;2-methoxy-3-hydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;3-hydroxy-20-epi-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;3-hydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-triene;2-methoxy-3-hydroxy-25-amino-26,27-bishomo-19-nor-cholesta-1,3,5(10)-triene;3-hydroxy-20-epi-25-amino-26,26-bishomo-19-nor-cholesta-1,3,5(10)-triene;3-hydroxy-25-acetylamino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;2-methoxy-3-hydroxy-25-acetylamino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;3-hydroxy-20-epi-25-acetylamino-26,27-bishomo-19-nor-cholest-1,3,5(10)trien-23-yne;3,22-dihydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;2-methoxy-3,22-dihydroxy-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;3,22-dihydroxy-20-epi-25-amino-26,27-bishomo-19-nor-cholest-1,3,5(10)-trien-23-yne;2-methoxy-3-hydroxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),16-tetraene;2-methoxy-3-hydroxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),16-tetraene;2-methoxy-3-hydroxy-25-acetylamino-19-nor-cholest-1,3,5(10),16-tetraene;2-methoxy-3-hydroxy-25-amino-19-nor-cholest-1,3,5(10),16-tetraene;3-hydroxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),6,8,16-hexaene;3-hydroxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),6,8,16-hexaene;3,25-dihydroxy-19-nor-cholest-1,3,5(10)-trien-23-yne;3,25-dihydroxy-19-nor-cholest-1,3,5(10)-triene;2-methoxy-3,25-dihydroxy-19-nor-cholest-1,3,5(10)-trien-23-yne;3,25-dihydroxy-20-epi-19-nor-cholest-1,3,5(10)-trien-23-yne;2-methoxy-3,25-dihydroxy-19-nor-cholest-1,3,5(10)-triene;3,25-dihydroxy-20-epi-19-nor-cholest-1,3,5(10)-triene;3,25-dihydroxy-24,24a-bishomo-19-nor-cholest-1,3,5(10),22,24(24a)-pentaene;25-amino-3-hydroxy-20-epi-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;25-acetylamino-3-hydroxy-20-epi-19-nor-cholest-1,3,5(10),16-tetraene;25-amino-3-hydroxy-20-epi-19-nor-cholest-1,3,5(10),16-tetraene;25-acetylamino-3-hydroxy-20-epi-24-homo-19-nor-cholest-1,3,5(10),16-tetraene;3-hydroxy-24-homo-25-acetylamino-19-nor-cholest-1,3,5(10),6,16-pentaene;and 3-hydroxy-24-homo-25-amino-19-nor-cholest-1,3,5(10),6,16-pentaene.17. Pharmaceutical compositions comprising an active compound of formula(I) as claimed in claim 1 in admixture with one or more physiologicallyacceptable carriers or excipients.
 18. A method of treatment of a humanor animal subject to promote wound healing comprising administering tosaid subject a therapeutically effective amount of an active compound offormula (I) as claimed in claim 1.